2021/05/15 更新

写真a

オノデラ オサム
小野寺 理
ONODERA Osamu
所属
脳研究所 教授
職名
教授
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外部リンク

学位

  • 博士(医学) ( 1993年3月   新潟大学 )

研究キーワード

  • intermediate filaments

  • unfolding protein

  • CREB依存性転写

  • 天然変性蛋白

  • UPS

  • MTOC

  • GFP

  • polygultamine

  • Molecular neurobiology

  • Huntington disease

  • マイクロアレイ

  • 血管性認知症

  • 炎症

  • DRPLA

  • XRCC1

  • aggresome

  • 包括脳ネットワーク

  • HTRA1

  • ALS

  • TDP-43

  • アプラタキシン

  • 核内小体

  • TGF-β

  • グリア

  • CAG繰り返し配列

  • DNA損傷修復

  • 封入体

  • 脳小血管

  • DNA修復

  • ポリグルタミン

  • 多系統萎縮症

  • 神経病態

  • 神経変性疾患

  • 筋萎縮性側索硬化症

  • スプライシング

  • 脊髄小脳変性症

研究分野

  • ライフサイエンス / 神経内科学

  • ライフサイエンス / 放射線科学

  • ライフサイエンス / 神経形態学

  • ライフサイエンス / 神経内科学

  • ライフサイエンス / 人体病理学

経歴(researchmap)

  • 新潟大学医歯学総合病院 副院長

    2020年7月 - 現在

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  • 新潟大学   脳研究所 臨床神経科学部門 脳神経内科学分野   教授

    2020年4月 - 現在

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  • 新潟大学脳研究所長

    2020年2月 - 現在

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  • 新潟大学   脳研究所 臨床神経科学部門 神経内科学分野   教授

    2016年4月 - 2020年3月

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  • 新潟大学 脳研究所 分子神経疾患資源解析学分野   Brain Research Institute   教授

    2010年10月 - 2016年3月

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  • 新潟大学脳研究所   Brain Research Institute   准教授

    2002年 - 2010年

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経歴

  • 新潟大学   脳研究所 臨床神経科学部門   教授

    2016年4月 - 現在

  • 新潟大学   脳研究所 生命科学リソース研究センター   教授

    2011年10月 - 2016年3月

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻   教授

    2011年10月 - 2016年3月

  • 新潟大学   医歯学総合研究科 医科学専攻   教授

    2011年10月 - 2016年3月

  • 新潟大学   脳研究所 生命科学リソース研究センター   准教授

    2002年5月 - 2011年9月

  • 新潟大学   脳研究所   助手

    1998年5月 - 2002年4月

  • 新潟大学   医学部附属病院   医員

    1997年11月 - 1998年4月

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学歴

  • 新潟大学

    1989年4月 - 1993年3月

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    国名: 日本国

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  • 新潟大学   医学部

    1981年4月 - 1987年3月

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    国名: 日本国

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所属学協会

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委員歴

  • Neurochemistry International   Associate Editor  

    2018年8月 - 現在   

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    団体区分:学協会

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  • 日本神経学会   理事  

    2018年5月 - 現在   

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    団体区分:学協会

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  • 日本認知症学会   理事  

    2017年10月 - 現在   

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    団体区分:学協会

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論文

  • Heterozygous Cysteine-sparing NOTCH3 Variant p.Val237Met in a Japanese Patient with Suspected Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report.

    Yuya Kano, Ikuko Mizuta, Akihiko Ueda, Hiroaki Nozaki, Keita Sakurai, Osamu Onodera, Yukio Ando, Kentaro Yamada, Hiroyuki Yuasa, Toshiki Mizuno

    Internal medicine (Tokyo, Japan)   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.

    DOI: 10.2169/internalmedicine.6096-20

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  • Progressive micrographia without parkinsonism caused by autoimmune brainstem encephalitis: A case report. 国際誌

    Ryutaro Hanyu, Masahiro Hatakeyama, Masaki Namekawa, Yutaka Otsu, Mayura Sukegawa, Hiromi Hashida, Izumi Kawachi, Masato Kanazawa, Osamu Onodera

    Clinical neurology and neurosurgery202   106496 - 106496   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.clineuro.2021.106496

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  • Genetic Variations and Neuropathologic Features of Patients With PRKN Mutations. 国際誌

    Naohiko Seike, Akio Yokoseki, Ryoko Takeuchi, Kento Saito, Hiroaki Miyahara, Akinori Miyashita, Tetsuhiko Ikeda, Izumi Aida, Takashi Nakajima, Masato Kanazawa, Masatoshi Wakabayashi, Yasuko Toyoshima, Hitoshi Takahashi, Riki Matsumoto, Tatsushi Toda, Osamu Onodera, Atsushi Ishikawa, Takeshi Ikeuchi, Akiyoshi Kakita

    Movement disorders : official journal of the Movement Disorder Society   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar.

    DOI: 10.1002/mds.28521

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  • Strategies to prevent hemorrhagic transformation after reperfusion therapies for acute ischemic stroke: A literature review. 国際誌

    Yutaka Otsu, Masaki Namekawa, Masafumi Toriyabe, Itaru Ninomiya, Masahiro Hatakeyama, Masahiro Uemura, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

    Journal of the neurological sciences419   117217 - 117217   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Reperfusion therapies by tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) have ushered in a new era in the treatment of acute ischemic stroke (AIS). However, reperfusion therapy-related HT remains an enigma. AIM: To provide a comprehensive review focused on emerging concepts of stroke and therapeutic strategies, including the use of protective agents to prevent HT after reperfusion therapies for AIS. METHODS: A literature review was performed using PubMed and the ClinicalTrials.gov database. RESULTS: Risk of HT increases with delayed initiation of tPA treatment, higher baseline glucose level, age, stroke severity, episode of transient ischemic attack within 7 days of stroke onset, and hypertension. At a molecular level, HT that develops after thrombolysis is thought to be caused by reactive oxygen species, inflammation, remodeling factor-mediated effects, and tPA toxicity. Modulation of these pathophysiological mechanisms could be a therapeutic strategy to prevent HT after tPA treatment. Clinical mechanisms underlying HT after MT are thought to involve smoking, a low Alberta Stroke Program Early CT Score, use of general anesthesia, unfavorable collaterals, and thromboembolic migration. However, the molecular mechanisms are yet to be fully investigated. Clinical trials with MT and protective agents have also been planned and good outcomes are expected. CONCLUSION: To fully utilize the easily accessible drug-tPA-and the high recanalization rate of MT, it is important to reduce bleeding complications after recanalization. A future study direction could be to investigate the recovery of neurological function by combining reperfusion therapies with cell therapies and/or use of pleiotropic protective agents.

    DOI: 10.1016/j.jns.2020.117217

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  • TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons. 査読 国際誌

    Seiichi Nagano, Junki Jinno, Rehab F Abdelhamid, Yinshi Jin, Megumi Shibata, Shohei Watanabe, Sachiko Hirokawa, Masatoyo Nishizawa, Kenji Sakimura, Osamu Onodera, Hironori Okada, Takashi Okada, Yuko Saito, Junko Takahashi-Fujigasaki, Shigeo Murayama, Shuji Wakatsuki, Hideki Mochizuki, Toshiyuki Araki

    Acta neuropathologica140 ( 5 ) 695 - 713   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.

    DOI: 10.1007/s00401-020-02205-y

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    その他リンク: http://link.springer.com/article/10.1007/s00401-020-02205-y/fulltext.html

  • Progressive supranuclear palsy: Neuropathology of patients with a short disease duration due to unexpected death 国際誌

    Lu Zhang, Yasuko Toyoshima, Akari Takeshima, Hiroshi Shimizu, Itsuro Tomita, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    NEUROPATHOLOGY   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Progressive supranuclear palsy (PSP) presents with a wide variety of signs/symptoms, making early initial diagnosis difficult. We investigated the clinical and neuropathological features of five patients with autopsy-proven PSP of short duration, ranging from 11 to 41 months (average, 26.2 months) due to unexpected death, focusing particularly on the distribution and severity of neuronal loss as well as neuronal and glial tau pathology in the affected brain. Clinical features were studied retrospectively through careful review of the medical records, and neuropathological examinations were carried out, along with tau immunohistochemistry using a monoclonal antibody AT8. These patients were diagnosed as having probable PSP (n = 4) and suggestive PSP (n = 1), respectively. In all cases, neuronal loss was evident in the substantia nigra, subthalamic nucleus, globus pallidus, and locus ceruleus. AT8-identified tau lesions, that is, pretangles/neurofibrillary tangles (PTs/NFTs), tufted astrocytes (TAs), and coiled bodies/neuropil threads (CBs/NTs), were distributed widely in the brain regions, especially in patients with longer disease duration. All cases showed variation in the regional tau burden among PTs/NFTs, TAs, and CBs/NTs. There was also a tendency for tau deposition to be more predominant in neuronal cells in the brainstem and cerebellum and in glial cells in the cerebral cortex and subcortical gray matter. These findings suggest that in PSP, the initial signs/symptoms are associated with degeneration and subsequent death of neurons with pathological tau deposition, and that the tau deposition in neuronal cells is independent of that in glial cells.

    DOI: 10.1111/neup.12707

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  • Association between serum IgG antibody titers against Porphyromonas gingivalis and liver enzyme levels: A cross-sectional study in Sado Island. 国際誌

    Kei Takamisawa, Noriko Sugita, Shigeki Komatsu, Minako Wakasugi, Akio Yokoseki, Akihiro Yoshihara, Tetsuo Kobayashi, Kazutoshi Nakamura, Osamu Onodera, Takeshi Momotsu, Naoto Endo, Kenji Sato, Ichiei Narita, Hiromasa Yoshie, Koichi Tabeta

    Heliyon6 ( 11 ) e05531   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

    DOI: 10.1016/j.heliyon.2020.e05531

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  • Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3. 国際誌

    Mercedes Prudencio, Hector Garcia-Moreno, Karen R Jansen-West, Rana Hanna Al-Shaikh, Tania F Gendron, Michael G Heckman, Matthew R Spiegel, Yari Carlomagno, Lillian M Daughrity, Yuping Song, Judith A Dunmore, Natalie Byron, Björn Oskarsson, Katharine A Nicholson, Nathan P Staff, Sorina Gorcenco, Andreas Puschmann, João Lemos, Cristina Januário, Mark S LeDoux, Joseph H Friedman, James Polke, Robin Labrum, Vikram Shakkottai, Hayley S McLoughlin, Henry L Paulson, Takuya Konno, Osamu Onodera, Takeshi Ikeuchi, Mari Tada, Akiyoshi Kakita, John D Fryer, Christin Karremo, Inês Gomes, John N Caviness, Mark R Pittelkow, Jan Aasly, Ronald F Pfeiffer, Venka Veerappan, Eric R Eggenberger, William D Freeman, Josephine F Huang, Ryan J Uitti, Klaas J Wierenga, Iris V Marin Collazo, Philip W Tipton, Jay A van Gerpen, Marka van Blitterswijk, Guojun Bu, Zbigniew K Wszolek, Paola Giunti, Leonard Petrucelli

    Science translational medicine12 ( 566 )   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

    DOI: 10.1126/scitranslmed.abb7086

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  • [Cell Therapy Using Peripheral Mononuclear Cells Preconditioned by Oxygen-Glucose Deprivation for Ischemic Stroke].

    Masahiro Hatakeyama, Itaru Ninomiya, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

    Brain and nerve = Shinkei kenkyu no shinpo72 ( 10 ) 1097 - 1103   2020年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Many studies in recent years have reported cell therapies using embryonic stem cells, induced pluripotent stem cells, and bone marrow-derived mononuclear cells for cerebral ischemia. However, obtaining these cells is challenging, and these cell therapies require complicated procedures to prepare cells for administration. Notably, peripheral blood mononuclear cells (PBMCs) are a useful cell source for clinical applications because cell collection is easier. In this review, we report the therapeutic effects of PBMCs preconditioned by oxygen-glucose deprivation (OGD-PBMCs) on cerebral ischemia. Cell therapies using tissue-protective OGD-PBMCs might be a simple and ideal therapeutic strategy against ischemic stroke.

    DOI: 10.11477/mf.1416201655

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  • A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. 国際誌

    Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

    Communications biology3 ( 1 ) 526 - 526   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

    DOI: 10.1038/s42003-020-01251-2

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  • Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review. 査読 国際誌

    Masahiro Hatakeyama, Itaru Ninomiya, Yutaka Otsu, Kaoru Omae, Yasuko Kimura, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata, Masato Kanazawa

    International journal of molecular sciences21 ( 17 )   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

    DOI: 10.3390/ijms21176194

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  • Novel CHP1 mutation in autosomal-recessive cerebellar ataxia: autopsy features of two siblings. 査読 国際誌

    Rie Saito, Norikazu Hara, Mari Tada, Yoshiaki Honma, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

    Acta neuropathologica communications8 ( 1 ) 134 - 134   2020年8月

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  • [Dural arteriovenous fistula causing complex visual hallucinations without an anopsia]. 査読

    Shingo Koide, Masahiro Hatakeyama, Masahiro Uemura, Bumpei Kikuchi, Hitoshi Hasegawa, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology60 ( 6 ) 425 - 428   2020年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We report the case of a 76-year-old woman who presented with recurrent episodes of complex visual hallucinations in her right visual field without an anopsia. The electroencephalogram showed sharp transients in the left parietotemporal region with phase reversals at T5 and P3. FLAIR MRI revealed hyperintense lesions in the left temporo-occipital lobe, located mainly in the left inferior temporal lobe. Cerebral angiography revealed an arteriovenous shunt from the left occipital artery to the left transverse sinus with cortical venous reflux. The complex visual hallucinations were resolved after transarterial embolization. We therefore hypothesize that this patient's complex visual hallucinations were caused by epileptic seizures or changes in cortical blood flow caused by the cortical venous reflux from the arteriovenous fistula. In general, epileptic hallucinations expand into the bilateral visual field. We reveal that in rare cases, complex visual hallucinations can also be limited to the unilateral visual field without an anopsia. Additionally, we reveal that a dural arteriovenous fistula can cause visual hallucinations without hemianopia.

    DOI: 10.5692/clinicalneurol.60.cn-001371

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  • Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: Clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP12. 査読 国際誌

    Rie Saito, Hiroshi Shimizu, Takeshi Miura, Norikazu Hara, Naomi Mezaki, Yo Higuchi, Akinori Miyashita, Izumi Kawachi, Kazuhiro Sanpei, Yoshiaki Honma, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita

    Acta neuropathologica communications8 ( 1 ) 75 - 75   2020年6月

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  • Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation. 査読 国際誌

    Eiko N Minakawa, Helena Akiko Popiel, Masayoshi Tada, Toshiaki Takahashi, Hiroshi Yamane, Yuji Saitoh, Yasuo Takahashi, Daisaku Ozawa, Akiko Takeda, Toshihide Takeuchi, Yuma Okamoto, Kazuhiro Yamamoto, Mari Suzuki, Hiromi Fujita, Chiyomi Ito, Hiroko Yagihara, Yuko Saito, Kei Watase, Hiroaki Adachi, Masahisa Katsuno, Hideki Mochizuki, Kentaro Shiraki, Gen Sobue, Tatsushi Toda, Keiji Wada, Osamu Onodera, Yoshitaka Nagai

    Brain : a journal of neurology143 ( 6 ) 1811 - 1825   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

    DOI: 10.1093/brain/awaa115

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  • Refractory Myositis Affecting the Intrinsic Muscles of the Hand. 査読

    Kosei Nakamura, Akihiro Sugai, Etsuji Saji, Kensaku Kasuga, Osamu Onodera

    Internal medicine (Tokyo, Japan)59 ( 9 ) 1211 - 1214   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

    DOI: 10.2169/internalmedicine.3773-19

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  • [Amyloid β-related angiitis presenting extensive brain involvement without detection of hemorrhagic lesions: A case report]. 査読

    Yuya Hatano, Akihiro Sugai, Takuma Yamagishi, Akihiro Nakajima, Akiyoshi Kakita, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology60 ( 3 ) 187 - 192   2020年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    In amyloid β-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid β-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid β-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

    DOI: 10.5692/clinicalneurol.cn-001340

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  • Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials. 査読 国際誌

    Masatoyo Nishizawa, Osamu Onodera, Akihiro Hirakawa, Yoshitaka Shimizu, Masayuki Yamada

    Journal of neurology, neurosurgery, and psychiatry91 ( 3 ) 254 - 262   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD). METHODS: Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305. RESULTS: From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was -0.61 (-1.64 vs -1.03; 95% CI -1.16 to -0.06; p=0.029) in the adjusted mean change in the SARA total score. CONCLUSIONS: Rovatirelin is a potentially effective treatment option for SCD. TRIAL REGISTRATION NUMBER: NCT01970098; NCT02889302.

    DOI: 10.1136/jnnp-2019-322168

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  • [Molecular mechanism of amyotrophic lateral sclerosis (ALS) from the viewpoint of the formation and degeneration of transactive response DNA-binding protein 43 kDa (TDP-43) inclusions]. 査読

    Sou Kasahara, Tomohiko Ishihara, Yuka Koike, Akihiro Sugai, Osamu Onodera

    Rinsho shinkeigaku = Clinical neurology60 ( 2 ) 109 - 116   2020年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.

    DOI: 10.5692/clinicalneurol.cn-001362

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  • Hemorrhagic cerebral small vessel disease caused by a novel mutation in 3' UTR of collagen type IV alpha 1. 査読 国際誌

    Naoko Sakai, Masahiro Uemura, Taisuke Kato, Hiroaki Nozaki, Akihide Koyama, Shouichirou Ando, Hiroyuki Kamei, Motohiro Kato, Osamu Onodera

    Neurology. Genetics6 ( 1 ) e383   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1212/NXG.0000000000000383

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  • Amyotrophic Lateral Sclerosis with Pallidonigroluysian Degeneration: A Clinicopathological Study. 査読 国際誌

    Junko Ito, Hiroshi Shimizu, Kentaro Ohta, Jiro Idezuka, Hajime Tanaka, Hiroshi Kondo, Takashi Nakajima, Hitoshi Takahashi, Kohei Akazawa, Osamu Onodera, Akiyoshi Kakita

    Annals of neurology87 ( 2 ) 302 - 312   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.

    DOI: 10.1002/ana.25652

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  • Transactive response DNA-binding protein 43kDa(TDP-43)凝集体の形成と分解からみたamyotrophic lateral sclerosis(ALS)の分子機構 査読

    笠原 壮, 石原 智彦, 小池 佑佳, 須貝 章弘, 小野寺 理

    臨床神経学60 ( 2 ) 109 - 116   2020年2月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

    孤発性筋萎縮性側索硬化症(sporadic amyotrophic lateral sclerosis;SALS)、および多くの家族性ALS(familial ALS;FALS)において、神経細胞質内transactive response DNA-binding protein 43kDa(TDP-43)陽性の封入体を認める。この事実からTDP-43は本症の根幹に関わる分子である。ALS病因遺伝子の機能解析から、TDP-43の病的凝集体形成/分解に関わる発症メカニズムの解明が進められている。凝集体形成の場として、非膜性構造であるストレス顆粒が注目されており、FUSやC9orf72の関与が示されている。一方、凝集体分解機構であるユビキチン-プロテアソーム系、オートファジー系に関わるALS病因遺伝子も報告されている。SALSおよびFALSに共通する分子病態に対する治療研究が進められている。(著者抄録)

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  • Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy

    Masahiro Uemura, Hiroaki Nozaki, Naoko Sakai, Shouichirou Ando, Masato Kanazawa, Hajime Kondo, Akira Iwanaga, Hiroyuki Murota, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

    STROKE51   2020年2月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Role of RNF213 p.4810K variant in the development of intracranial arterial disease in patients treated with nilotinib. 査読 国際誌

    Masahiro Uemura, Masato Kanazawa, Takuma Yamagishi, Takahiro Nagai, Mami Takahashi, Shingo Koide, Masayoshi Tada, Junsuke Shimbo, Aiko Isami, Kunihiko Makino, Masayoshi Masuko, Kouji Nikkuni, Kouichirou Okamoto, Shuichi Igarashi, Kenichi Morita, Osamu Onodera

    Journal of the neurological sciences408   116577 - 116577   2020年1月

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  • Progressive Supranuclear Palsy with Predominant Cerebellar Ataxia. 査読 国際誌

    Shoichiro Ando, Masato Kanazawa, Osamu Onodera

    Journal of movement disorders13 ( 1 ) 20 - 26   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

    DOI: 10.14802/jmd.19061

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  • Excessive Production of Transforming Growth Factor β1 Causes Mural Cell Depletion From Cerebral Small Vessels. 査読 国際誌

    Taisuke Kato, Yumi Sekine, Hiroaki Nozaki, Masahiro Uemura, Shoichiro Ando, Sachiko Hirokawa, Osamu Onodera

    Frontiers in aging neuroscience12   151 - 151   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer's disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

    DOI: 10.3389/fnagi.2020.00151

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  • A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan. 査読 国際誌

    Akihiro Shindo, Ken-Ichi Tabei, Akira Taniguchi, Hiroaki Nozaki, Osamu Onodera, Akihiko Ueda, Yukio Ando, Takao Urabe, Kazumi Kimura, Kazuo Kitagawa, Haruo Hanyu, Teruyuki Hirano, Hideaki Wakita, Hidenao Fukuyama, Tatsuo Kagimura, Yoshihiro Miyamoto, Misa Takegami, Satoshi Saito, Akiko Watanabe-Hosomi, Ikuko Mizuta, Masafumi Ihara, Toshiki Mizuno, Hidekazu Tomimoto

    Frontiers in aging neuroscience12   216 - 216   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

    DOI: 10.3389/fnagi.2020.00216

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  • HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. 査読 国際誌

    Masahiro Uemura, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Nozomi Hishikawa, Yoshinori Nishimoto, Kiran Polavarapu, Atchayaram Nalini, Akira Hanazono, Daisuke Kuzume, Akihiro Shindo, Mohammad El-Ghanem, Arata Abe, Aki Sato, Mari Yoshida, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

    Frontiers in neurology11   545 - 545   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

    DOI: 10.3389/fneur.2020.00545

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  • Publisher Correction: A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation. 査読 国際誌

    Masahiro Hatakeyama, Masato Kanazawa, Itaru Ninomiya, Kaoru Omae, Yasuko Kimura, Tetsuya Takahashi, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata

    Scientific reports9 ( 1 ) 19913 - 19913   2019年12月

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    記述言語:英語  

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    DOI: 10.1038/s41598-019-55308-2

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  • A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation. 査読 国際誌

    Masahiro Hatakeyama, Masato Kanazawa, Itaru Ninomiya, Kaoru Omae, Yasuko Kimura, Tetsuya Takahashi, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata

    Scientific reports9 ( 1 ) 16819 - 16819   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

    DOI: 10.1038/s41598-019-53418-5

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  • [Molecular Pathogenesis of Amyotrophic Lateral Sclerosis]. 査読

    Shintaro Tsuboguchi, Tomohiko Ishihara, Akihiro Sugai, Akio Yokoseki, Osamu Onodera

    Brain and nerve = Shinkei kenkyu no shinpo71 ( 11 ) 1183 - 1189   2019年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.

    DOI: 10.11477/mf.1416201428

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  • Shrinkage of the myenteric neurons of the small intestine in patients with multiple system atrophy. 査読 国際誌

    Tetsutaro Ozawa, Hiroshi Shimizu, Hideaki Matsui, Osamu Onodera, Akiyoshi Kakita

    Autonomic neuroscience : basic & clinical221   102583 - 102583   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed to determine whether enteric neurons are involved in multiple system atrophy (MSA). Four-μm-thick slices of small intestine were prepared from 10%-formalin-fixed and paraffin-embedded materials obtained from autopsied cases. Enteric neurons were stained using an anti-peripherin antibody. Immunostaining of phosphorylated α-synuclein was also performed. Areas of the cytoplasm and nucleus that showed nucleoli were measured using computer software. Both areas of myenteric neurons were significantly smaller in MSA cases (n = 3) than in control subjects (n = 3) (P < 0.0001); however, no deposits of phosphorylated α-synuclein were observed. These findings suggest that myenteric neurons in MSA are affected independent of α-synuclein accumulation.

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  • 【ALS 2019】TDP-43封入体から解くALSの分子病態 査読

    坪口 晋太朗, 石原 智彦, 須貝 章弘, 横関 明男, 小野寺 理

    BRAIN and NERVE: 神経研究の進歩71 ( 11 ) 1183 - 1189   2019年11月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

    <文献概要>TDP-43蛋白質の封入体形成機構は,筋萎縮性側索硬化症(ALS)の主要な分子病態機序である。ALS原因遺伝子の機能解析から,TDP-43封入体形成にはストレス顆粒形成,蛋白質分解機構,TDP-43蛋白質の自己調節機構の破綻などが関わることが見出された。これらの解明された分子病態に基づく,ALS治療方法の確立が期待される。

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  • Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. 査読 国際誌

    Fumiaki Mori, Mari Tada, Tomoya Kon, Yasuo Miki, Kunikazu Tanji, Hidekachi Kurotaki, Masahiko Tomiyama, Tomohiko Ishihara, Osamu Onodera, Akiyoshi Kakita, Koichi Wakabayashi

    Acta neuropathologica communications7 ( 1 ) 165 - 165   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. AIM: The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. MATERIAL AND METHODS: Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). RESULTS: Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. CONCLUSION: The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

    DOI: 10.1186/s40478-019-0824-1

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  • Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III). 査読 国際誌

    H Tanaka, Y Toyoshima, S Kawakatsu, R Kobayashi, O Yokota, S Terada, S Kuroda, T Miura, Y Higuchi, H Otsu, K Sanpei, K Otani, T Ikeuchi, O Onodera, A Kakita, H Takahashi

    Neuropathology and applied neurobiology   2019年10月

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    記述言語:英語  

    AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

    DOI: 10.1111/nan.12581

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  • Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. 査読 国際誌

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Neurobiology of disease130   104534 - 104534   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

    DOI: 10.1016/j.nbd.2019.104534

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  • Ectopic Expression Induces Abnormal Somatodendritic Distribution of Tau in the Mouse Brain. 査読 国際誌

    Atsuko Kubo, Shouyou Ueda, Ayaka Yamane, Satoko Wada-Kakuda, Mai Narita, Makoto Matsuyama, Akane Nomori, Akihiko Takashima, Taisuke Kato, Osamu Onodera, Motohito Goto, Mamoru Ito, Takami Tomiyama, Hiroshi Mori, Shigeo Murayama, Yasuo Ihara, Hiroaki Misonou, Tomohiro Miyasaka

    The Journal of neuroscience : the official journal of the Society for Neuroscience39 ( 34 ) 6781 - 6797   2019年8月

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    記述言語:英語  

    Tau is a microtubule (MT)-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mislocalization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but also the pre-aggregated tau in mouse brain tissues of both sexes. Using these antibodies, we found that in tau-transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mislocalization in the transgenic mice. Superresolution microscopic and biochemical analyses also indicated that the interaction between MTs and exogenous tau was impaired only in the tau-transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mislocalization, a key step of the tauopathy.SIGNIFICANCE STATEMENT Somatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mislocalization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (e.g., human tau in transgenic mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

    DOI: 10.1523/JNEUROSCI.2845-18.2019

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  • 【細胞内の相分離 タンパク質や核酸分子を整理し、反応の場を作り、生命を駆動する】ALS病態における液-液相分離と非膜性構造の異常 査読

    小池 佑佳, 石原 智彦, 小野寺 理

    実験医学37 ( 9 ) 1416 - 1420   2019年6月

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    記述言語:日本語   出版者・発行元:(株)羊土社  

    TDP-43やFUSに代表される、筋萎縮性側索硬化症(ALS)関連タンパク質の多くは、RNA結合タンパク質であり、複数の生体高分子と凝集し、非膜性の集合体を形成する。この現象は液-液相分離(LLPS)とよばれる。LLPSと類似の挙動を呈する非膜性の細胞構造の一つであるGEM小体は、スプライソソーム成熟に寄与する。われわれは、TDP-43発現抑制細胞とALS患者由来組織において、GEM小体数減少を示した。このことは、ALS関連タンパク質の機能喪失により、スプライソソーム機能不全を介したスプライシング破綻が生じることを示す。(著者抄録)

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  • Angiogenesis in the ischemic core: A potential treatment target? 査読 国際誌

    Masato Kanazawa, Tetsuya Takahashi, Masanori Ishikawa, Osamu Onodera, Takayoshi Shimohata, Gregory J Del Zoppo

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism39 ( 5 ) 753 - 769   2019年5月

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    記述言語:英語  

    The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

    DOI: 10.1177/0271678X19834158

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  • Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases. 査読 国際誌

    Hidetomo Tanaka, Shinobu Kawakatsu, Yasuko Toyoshima, Takeshi Miura, Naomi Mezaki, Atsushi Mano, Kazuhiro Sanpei, Ryota Kobayashi, Hiroshi Hayashi, Koichi Otani, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    Neuropathology : official journal of the Japanese Society of Neuropathology39 ( 2 ) 111 - 119   2019年4月

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    記述言語:英語  

    Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

    DOI: 10.1111/neup.12532

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  • Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy. 査読 国際誌

    Koji Kato, Ryo Maemura, Manabu Wakamatsu, Ayako Yamamori, Motoharu Hamada, Shinsuke Kataoka, Atsushi Narita, Shunsuke Miwata, Yuko Sekiya, Nozomu Kawashima, Kyogo Suzuki, Kotaro Narita, Sayoko Doisaki, Hideki Muramatsu, Hirotoshi Sakaguchi, Kimikazu Matsumoto, Yuka Koike, Osamu Onodera, Makiko Kaga, Nobuyuki Shimozawa, Nao Yoshida

    Molecular genetics and metabolism reports18   1 - 6   2019年3月

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    記述言語:英語  

    Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

    DOI: 10.1016/j.ymgmr.2018.11.001

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  • Low serum 25-hydroxyvitamin D increases cognitive impairment in elderly people. 査読

    Mayumi Sakuma, Kaori Kitamura, Naoto Endo, Takeshi Ikeuchi, Akio Yokoseki, Osamu Onodera, Takeo Oinuma, Takeshi Momotsu, Kenji Sato, Kazutoshi Nakamura, Ichiei Narita

    Journal of bone and mineral metabolism37 ( 2 ) 368 - 375   2019年3月

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    記述言語:英語  

    It has been reported that many elderly people have low serum levels of 25-hydroxyvitamin D [25(OH)D] and that serum 25(OH)D levels may have a relationship with cognitive function. The aim of this study was to examine the relationship between serum 25(OH)D levels and cognitive function in a Japanese population. This cross-sectional study was performed as a part of the Project in Sado for Total Health (PROST). The PROST study evaluated cognitive state and serum vitamin D level from June 2011 to November 2013 for 740 patients (431 men and 309 women). The Mini-Mental State Examination-Japanese version (MMSE-J) and serum 25(OH)D level measurements were used as assessment tools. Cognitive impairment was defined using MMSE-J ≤ 23 as a cutoff. Multiple logistic regression analyses were performed to calculate the odds ratios (ORs) for low MMSE-J scores. The average subject age was 68.1 years, the average MMSE- J score was 25.9, and the average 25(OH)D level was 24.6 ng/mL. Significant ORs for cognitive impairment were observed for both high age and low serum 25(OH)D. The adjusted OR for the lowest versus highest serum 25(OH)D quartiles was 2.70 (95% confidence interval 1.38-5.28, P = 0.0110). Low serum 25(OH)D levels were independently associated with a higher prevalence of cognitive impairment.

    DOI: 10.1007/s00774-018-0934-z

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  • 【神経疾患とトレース・メタル-知っていますか?】鉄 Friedreich失調症と鉄代謝 査読

    坪口 晋太朗, 石原 智彦, 小野寺 理

    Clinical Neuroscience37 ( 3 ) 308 - 310   2019年3月

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    記述言語:日本語   出版者・発行元:(株)中外医学社  

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  • Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation. 査読 国際誌

    Rie Saito, Hiroaki Nozaki, Taisuke Kato, Yasuko Toyoshima, Hajime Tanaka, Yutaka Tsubata, Tetsuo Morioka, Yoh Horikawa, Kiyomitsu Oyanagi, Takashi Morita, Osamu Onodera, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology78 ( 2 ) 181 - 186   2019年2月

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    記述言語:英語  

    Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.

    DOI: 10.1093/jnen/nly115

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  • Neuropathologic characteristics of patients with progressive suprenuclear palsy who died within four years after the disease onset

    Lu Zhang, Yasuko Toyoshima, Akari Takeshima, Hiroshi Shimizu, Itsuro Tomita, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    BRAIN PATHOLOGY29   77 - 77   2019年2月

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    記述言語:英語   出版者・発行元:WILEY  

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  • Radiological, immunological, and pathological analysis of ependymal cells in neuromyelitis spectrum disorders

    Fumihiro Yanagimura, Etsuji Saji, Takahiro Wakasugi, Yasuko Toyoshima, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Izumi Kawachi

    BRAIN PATHOLOGY29   134 - 134   2019年2月

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    記述言語:英語   出版者・発行元:WILEY  

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  • HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade. 査読 国際誌

    Masahiro Uemura, Hiroaki Nozaki, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Taisuke Kato, Osamu Onodera

    Frontiers in neurology10   693 - 693   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers. The molecular differences between the mutations identified in symptomatic carriers and mutations identified only in CARASIL patients are unclear. HTRA1 is a serine protease that forms homotrimers, with each HTRA1 subunit activating the adjacent HTRA1 via the sensor domain of loop 3 (L3) and the activation domain of loop D (LD). Previously, we analyzed four HTRA1 mutant proteins identified in symptomatic carriers and found that they were unable to form trimers or had mutations in the LD or L3 domain. The mutant HTRA1s with these properties are presumed to inhibit trimer-dependent activation cascade. Indeed, these mutant HTRA1s inhibited wild-type (WT) protease activity. In this study, we further analyzed 15 missense HTRA1s to clarify the molecular character of mutant HTRA1s identified in symptomatic carriers. Methods: We analyzed 12 missense HTRA1s identified in symptomatic carriers (hetero-HTRA1) and three missense HTRA1s found only in CARASIL (CARASIL-HTRA1). The protease activity of the purified recombinant mutant HTRA1s was measured using fluorescein isothiocyanate-labeled casein as substrate. Oligomeric structure was evaluated by size-exclusion chromatography. The protease activities of mixtures of WT with each mutant HTRA1 were also measured. Results: Five hetero-HTRA1s had normal protease activity and were excluded from further analysis. Four of the seven hetero-HTRA1s and one of the three CARASIL-HTRA1s were unable to form trimers. The other three hetero-HTRA1s had mutations in the LD domain. Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (P = 0.162). Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1.

    DOI: 10.3389/fneur.2019.00693

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  • Is the population of Sado Island genetically close to the population of western Japan? 査読 国際誌

    Kazuharu Misawa, Hiroshi Watanabe, Akio Yokoseki, Minako Wakasugi, Osamu Onodera, Ichiei Narita, Takeshi Momotsu, Kenji Sato, Naoto Endo

    Human genome variation6   26 - 26   2019年

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    記述言語:英語  

    To explore the effect of aging, a cohort study is being performed on Sado Island, which is located in the Sea of Japan. Sado Island is close to the eastern coast of Japan, yet its population speaks the western Japanese dialect. Consequently, the genetic background of the population of Sado Island is of interest. Based on Nei's genetic distance, we compared the allele frequencies of people from Sado Island to those of people from Nagahama and Miyagi, which are located in the western and northeastern parts of Honshu, respectively. The results showed that the populations of Miyagi and Nagahama are genetically closer to each other than to the population of Sado Island. Because the Sado and Honshu Islands are isolated by a channel, it is possible that genetic drift occurred within Sado Island, which would explain the uniqueness of the people of this region.

    DOI: 10.1038/s41439-019-0058-6

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  • Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy. 査読 国際誌

    Naomi Mezaki, Takeshi Miura, Kotaro Ogaki, Makoto Eriguchi, Yuri Mizuno, Kenichi Komatsu, Hiroki Yamazaki, Natsuki Suetsugi, Sumihiro Kawajiri, Ryo Yamasaki, Takanobu Ishiguro, Takuya Konno, Hiroaki Nozaki, Kensaku Kasuga, Yasuyuki Okuma, Jun-Ichi Kira, Hideo Hara, Osamu Onodera, Takeshi Ikeuchi

    Neurology. Genetics4 ( 6 ) e292   2018年12月

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    記述言語:英語  

    Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

    DOI: 10.1212/NXG.0000000000000292

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  • CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases 査読 国際誌

    Akihiko Yuki, Satoru Shinkuma, Ryota Hayashi, Hiroki Fujikawa, Taisuke Kato, Erina Homma, Yohei Hamade, Osamu Onodera, Masao Matsuoka, Hiroshi Shimizu, Hiroaki Iwata, Riichiro Abe

    JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY79 ( 6 ) 1039 - 1046   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MOSBY-ELSEVIER  

    Background: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Early-stage MF patches or plaques often resemble inflammatory skin disorders (ISDs), including psoriasis and atopic dermatitis. Cell adhesion molecule 1 gene (CADM1), which was initially identified as a tumor suppressor gene in human non-small cell lung cancer, has been reported as a diagnostic marker for adult T-cell leukemia/lymphoma.Objective: We investigated CADM1 expression in MF neoplastic cells, especially during early stages, and evaluated its usefulness as a diagnostic marker for MF.Methods: We conducted a retrospective study by using immunohistochemical staining and confirmed the expression of CADM1 in MF. In addition, we compared CADM1 messenger RNA expression in microdissected MF samples and ISD samples.Results: In the overall study period, 55 of 58 MF samples (94.8%) stained positive for CADM1. None of the 50 ISD samples showed positive reactivity (P < .0001). We found CADM1 messenger RNA expression in the intradermal lymphocytes of patients with MF but not in those of patients with an ISD.Limitations: We did not conduct a validation study for MF cases in other institutions.Conclusions: CADM1-positive cells can be identified in early stages with fewer infiltrating cells and may be useful as a diagnostic marker for early-stage MF.

    DOI: 10.1016/j.jaad.2018.06.025

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  • 本邦におけるCADASILの現状 査読

    新堂 晃大, 田部井 賢一, 谷口 彰, 小野寺 理, 猪原 匡史, 水野 敏樹, 冨本 秀和

    臨床神経学58 ( Suppl. ) S310 - S310   2018年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years. 査読 国際誌

    Junko Ito, Tetsuro Shimada, Mari Tada, Hiroshi Shimizu, Masatoshi Wakabayashi, Akio Yokoseki, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology77 ( 11 ) 981 - 986   2018年11月

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    記述言語:英語  

    We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

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  • Identification and functional characterization of novel mutations including frameshift mutation in exon 4 of CSF1R in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. 査読 国際誌

    Takeshi Miura, Naomi Mezaki, Takuya Konno, Akio Iwasaki, Naoyuki Hara, Masatomo Miura, Michitaka Funayama, Yuki Unai, Yuichi Tashiro, Kenji Okita, Takeshi Kihara, Nobuo Ito, Yoichi Kanatsuka, David T Jones, Norikazu Hara, Takanobu Ishiguro, Takayoshi Tokutake, Kensaku Kasuga, Hiroaki Nozaki, Dennis W Dickson, Osamu Onodera, Zbigniew K Wszolek, Takeshi Ikeuchi

    Journal of neurology265 ( 10 ) 2415 - 2424   2018年10月

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    記述言語:英語  

    OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

    DOI: 10.1007/s00415-018-9017-2

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  • Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation. 査読 国際誌

    Junko Ito, Hiroaki Nozaki, Yasuko Toyoshima, Takashi Abe, Aki Sato, Hideki Hashidate, Shuichi Igarashi, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Neuropathology : official journal of the Japanese Society of Neuropathology   2018年5月

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    記述言語:英語  

    Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

    DOI: 10.1111/neup.12473

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  • Predictors of cognitive impairment in multiple system atrophy. 査読 国際誌

    Masahiro Hatakeyama, Tomoe Sato, Tetsuya Takahashi, Masato Kanazawa, Osamu Onodera, Masatoyo Nishizawa, Takayoshi Shimohata

    Journal of the neurological sciences388   128 - 132   2018年5月

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    記述言語:英語  

    OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

    DOI: 10.1016/j.jns.2018.03.017

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  • Loss of Motor Neurons Innervating Cervical Muscles in Patients With Multiple System Atrophy and Dropped Head. 査読 国際誌

    Rie Saito, Mari Tada, Yasuko Toyoshima, Masatoyo Nishizawa, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology77 ( 4 ) 317 - 324   2018年4月

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    記述言語:英語  

    We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 ± 91.4 vs 521.3 ± 74.8, p = 0.0030, and 26.2 ± 9.1 vs 88.0 ± 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 ± 7.6 vs 288.7 ± 74.6, p = 0.048, and 18.0 ± 4.1 vs 34.3 ± 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA.

    DOI: 10.1093/jnen/nly007

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  • Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. 査読 国際誌

    Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu W, Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y, Date H, Matsukawa T, Kanda J, Nakamoto FK, Higashihara M, Abe K, Koike R, Sasagawa M, Kuroha Y, Hasegawa N, Kanesawa N, Kondo T, Hitomi T, Tada M, Takano H, Saito Y, Sanpei K, Onodera O, Nishizawa M, Nakamura M, Yasuda T, Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S, Yamasaki R, Tamaoka A, Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J, Morishita S, Tsuji S

    Nature genetics50 ( 4 ) 581 - 590   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41588-018-0067-2

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  • Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. 査読 国際誌

    Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue

    Neurobiology of aging64   158.e15-158.e19 - 158.e19   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

    DOI: 10.1016/j.neurobiolaging.2017.12.005

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  • Case Report: A patient with spinocerebellar ataxia type 31 and sporadic Creutzfeldt-Jakob disease. 査読 国際誌

    Natsumi Saito, Tomohiko Ishihara, Kensaku Kasuga, Mana Nishida, Takanobu Ishiguro, Hiroaki Nozaki, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa

    Prion12 ( 2 ) 147 - 149   2018年3月

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    記述言語:英語  

    We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.

    DOI: 10.1080/19336896.2018.1436926

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  • Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

    T. Konno, K. Yoshida, I. Mizuta, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology25 ( 1 ) 142 - 147   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

    DOI: 10.1111/ene.13464

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  • Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation 査読

    T. Konno, K. Yoshida, I. Mizuta, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology25 ( 1 ) 142 - 147   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

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  • Operation of a P300-based brain-computer interface in patients with Duchenne muscular dystrophy 査読 国際誌

    Kota Utsumi, Kouji Takano, Yoji Okahara, Tetsuo Komori, Osamu Onodera, Kenji Kansaku

    SCIENTIFIC REPORTS8 ( 1 ) 1753 - 1753   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    A brain-computer interface (BCI) or brain-machine interface is a technology that enables the control of a computer and other external devices using signals from the brain. This technology has been tested in paralysed patients, such as those with cervical spinal cord injuries or amyotrophic lateral sclerosis, but it has not been tested systematically in Duchenne muscular dystrophy (DMD), which is a severe type of muscular dystrophy due to the loss of dystrophin and is often accompanied by progressive muscle weakness and wasting. Here, we investigated the efficacy of a P300-based BCI for patients with DMD. Eight bedridden patients with DMD and eight age-and gender-matched able-bodied controls were instructed to input hiragana characters. We used a region-based, two-step P300-based BCI with green/blue flicker stimuli. EEG data were recorded, and a linear discriminant analysis distinguished the target from other non-targets. The mean online accuracy of inputted characters (accuracy for the two-step procedure) was 71.6% for patients with DMD and 80.6% for controls, with no significant difference between the patients and controls. The P300-based BCI was operated successfully by individuals with DMD in an advanced stage and these findings suggest that this technology may be beneficial for patients with this disease.

    DOI: 10.1038/s41598-018-20125-6

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  • Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data. 査読 国際誌

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Frontiers in neuroscience12   28 - 28   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

    DOI: 10.3389/fnins.2018.00028

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  • CARASIL families from India with 3 novel null mutations in the HTRA1 gene. 査読 国際誌

    Veeramani Preethish-Kumar, Hiroaki Nozaki, Sarbesh Tiwari, Seena Vengalil, Maya Bhat, Chandrajit Prasad, Osamu Onodera, Masahiro Uemura, Seshagiri Doniparthi, Jitender Saini, Saraswati Nashi, Kiran Polavarapu, Atchayaram Nalini

    Neurology89 ( 23 ) 2392 - 2394   2017年12月

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  • Clinical/scientific notes 査読

    Veeramani Preethish-Kumar, Hiroaki Nozaki, Sarbesh Tiwari, Seena Vengalil, Maya Bhat, Chandrajit Prasad, Osamu Onodera, Masahiro Uemura, Seshagiri Doniparthi, Jitender Saini, Saraswati Nashi, Kiran Polavarapu, Atchayaram Nalini

    Neurology89 ( 23 ) 2392 - 2394   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Lippincott Williams and Wilkins  

    DOI: 10.1212/WNL.0000000000004710

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  • The SMN gene copy number states in Japanese ALS patients

    Ishihara T, Toyoda S, Koyama A, Tada M, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Kakita A, Sobue G, Nishizawa M, Onodera O

    JOURNAL OF THE NEUROLOGICAL SCIENCES381   211-211   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jns.2017.08.604

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  • New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. 査読 国際誌

    Ikuko Mizuta, Akiko Watanabe-Hosomi, Takashi Koizumi, Mao Mukai, Ai Hamano, Yasuhiro Tomii, Masaki Kondo, Masanori Nakagawa, Hidekazu Tomimoto, Teruyuki Hirano, Makoto Uchino, Osamu Onodera, Toshiki Mizuno

    Journal of the neurological sciences381   62 - 67   2017年10月

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    記述言語:英語  

    PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

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  • Apparent diffusion coefficient reduction might be a predictor of poor outcome in patients with posterior reversible encephalopathy syndrome. 査読 国際誌

    Itaru Ninomiya, Masato Kanazawa, Yasuhisa Akaiwa, Takayoshi Shimohata, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa

    Journal of the neurological sciences381   1 - 3   2017年10月

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    記述言語:英語  

    It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p<0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES.

    DOI: 10.1016/j.jns.2017.08.002

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  • Association between dialysis treatment and cognitive decline: A study from the Project in Sado for Total Health (PROST), Japan 査読

    Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Keiko Kabasawa, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichici Narita, Naoto Endo

    GERIATRICS & GERONTOLOGY INTERNATIONAL17 ( 10 ) 1584 - 1587   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Aim: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan.Methods: This was a cross-sectional substudy of the Project in Sado for Total Etealth (PROST). Total Etealth PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score <24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease.Results: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates.Conclusion: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan..

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  • Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease 査読

    Kahori Shiba-Fukushima, Kei-Ichi Ishikawa, Tsuyoshi Inoshita, Nana Izawa, Masashi Takanashi, Shigeto Sato, Osamu Onodera, Wado Akamatsu, Hideyuki Okano, Yuzuru Imai, Nobutaka Hattori

    HUMAN MOLECULAR GENETICS26 ( 16 ) 3172 - 3185   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (Delta Psi m)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon Delta Psi m reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

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  • [Overview of Hereditary Spinocerebellar Ataxias in Japan]. 査読

    Masayoshi Tada, Akio Yokoseki, Osamu Onodera

    Brain and nerve = Shinkei kenkyu no shinpo69 ( 8 ) 879 - 890   2017年8月

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    記述言語:日本語  

    Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.

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  • The Clinical Features, Risk Factors, and Surgical Treatment of Cervicogenic Headache in Patients With Cervical Spine Disorders Requiring Surgery 査読

    Keiko Shimohata, Kazuhiro Hasegawa, Osamu Onodera, Masatoyo Nishizawa, Takayoshi Shimohata

    HEADACHE57 ( 7 ) 1109 - 1117   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Objective.-To clarify the clinical features and risk factors of cervicogenic headache (CEH; as diagnosed according to the International Classification of Headache Disorders-Third Edition beta) in patients with cervical spine disorders requiring surgery.
    Background.-CEH is caused by cervical spine disorders. The pathogenic mechanism of CEH is hypothesized to involve a convergence of the upper cervical afferents from the C1, C2, and C3 spinal nerves and the trigeminal afferents in the trigeminocervical nucleus of the upper cervical cord. According to this hypothesis, functional convergence of the upper cervical and trigeminal sensory pathways allows the bidirectional (afferent and efferent) referral of pain to the occipital, frontal, temporal, and/or orbital regions. Previous prospective studies have reported an 86-88% prevalence of headache in patients with cervical myelopathy or radiculopathy requiring anterior cervical surgery; however, these studies did not diagnose headache according to the International Classification of Headache Disorders criteria. Therefore, a better understanding of the prevalence rate, clinical features, risk factors, and treatment responsiveness of CEH in patients with cervical spine disorders requiring surgery is necessary.
    Methods.-We performed a single hospital-based prospective cross-sectional study and enrolled 70 consecutive patients with cervical spine disorders such as cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, cervical spondylotic radiculopathy, and cervical spondylotic myeloradiculopathy who had been scheduled to undergo anterior cervical fusion or dorsal cervical laminoplasty between June 2014 and December 2015. Headache was diagnosed preoperatively according to the International Classification of Headache Disorders-Third Edition beta. The Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, Neck Disability Index, and a 0-100 mm visual analog scale (VAS) were used to evaluate clinical features, and scores were compared between baseline (ie, preoperatively) and 3, 6, and 12 months post-surgery.
    Results.-The prevalence of CEH in our population was 15/70 (21.4%, 95% CI: 11.8% to 31.0%). The main clinical features were dull and tightening/pressing headache sensations in the occipital region. Headache severity was mild (VAS, 32611 mm) and only one patient reported use of an oral analgesic. Compared to patients without CEH, patients with CEH had higher frequencies of neck pain (86.7% vs. 50.9%; P=.017), cervical range of motion limitation (ROM) (66.7% vs. 38.2%; P=.049), and higher Neck Disability Index scores (14 vs. 3; P&lt;.001). Among the different cervical spine disorders, the prevalence of CEH was highest in cervical spondylotic myeloradiculopathy patients (60%), being &lt;= 20% for all other disorders. Surgical treatments including cervical laminoplasty to relieve abnormal pressure on the spinal cord via a posterior approach, were associated with initial improvements in headache VAS that slightly diminished by 12 months post-surgery (P&lt;.001).
    Conclusions.-We report a lower prevalence of CEH in patients with cervical spinal disorders requiring surgery than that reported previously. The main clinical features of CEH were mild, dull, and tightening/pressing headache sensations in the occipital region. Potential risk factors for CEH included neck pain, limited cervical ROM, high Neck Disability Index score, and a diagnosis of cervical spondylotic myeloradiculopathy. The further accumulation of patients in a multi-institutional study may be required in order to discuss the diagnostic criteria and pathophysiology of this condition.

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  • Multiple system atrophy: clinicopathological characteristics in Japanese patients 査読

    Tetsutaro Ozawa, Osamu Onodera

    PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES93 ( 5 ) 251 - 258   2017年5月

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    記述言語:英語   出版者・発行元:JAPAN ACAD  

    Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that has both clinical and pathological variants. Clinical examples include MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P), whereas olivopontocerebellar atrophy and striatonigral degeneration represent pathological variants. We performed systematic reviews of studies that addressed the relative frequencies of clinical or pathological variants of MSA in various populations to determine the clinicopathological characteristics in Japanese MSA. The results revealed that the majority of Japanese patients have MSA-C, while the majority of patients in Europe and North America have MSA-P. A comparative study of MSA pathology showed that the olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than in British MSA. Demonstrated differences in pathological subtype thus appear consistent with differences in the clinical subtype of MSA demonstrated between Japan and European populations. We concluded that olivopontocerebellar-predominant pathology and MSA-C may represent clinicopathological characteristics in Japanese MSA. Factors determining predominant involvement of olivopontocerebellar regions in MSA should therefore be explored.

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  • [PRES: Posterior Reversible Encephalopathy Syndrome]. 査読

    Kouichirou Okamoto, Kunio Motohashi, Hidemoto Fujiwara, Tomohiko Ishihara, Itaru Ninomiya, Osamu Onodera, Yukihiko Fujii

    Brain and nerve = Shinkei kenkyu no shinpo69 ( 2 ) 129 - 141   2017年2月

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    記述言語:日本語  

    Posterior reversible encephalopathy syndrome (PRES) is suggested in patients with acute neurological symptoms in the appropriate clinical context, including acute hypertension, blood pressure fluctuations, renal failure, blood transfusion, immunosuppression, autoimmune disorders, and eclampsia. PRES is a clinical syndrome, and refers to a disorder with reversible subcortical vasogenic brain edema caused by endothelial dysfunction, predominantly involving the bilateral parieto-occipital regions. Although the clinical course and prognosis are favorable in most cases, intracranial hemorrhage and/or restricted diffusion similar to acute infarction could be seen in some lesions on brain magnetic resonance imaging (MRI). The spinal cord may be involved in some patients with posterior fossa lesions. Understanding the pathophysiology of PRES is helpful in making the correct early diagnosis and selecting appropriate therapies to improve its clinical course and outcome. Differentiation of PRES from strokes is critical in the setting of a neurological emergency.

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  • Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: Multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions 査読

    Haishan Jiang, Hiroshi Shimizu, Atsushi Shiga, Masami Tanaka, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY37 ( 1 ) 69 - 77   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    We previously reported familial amyotrophic lateral sclerosis (FALS) of 11years duration in a 57-year-old woman, who received artificial ventilation for 5years prior to death and exhibited widespread multisystem degeneration and neurofilamentous aggregates, so-called conglomerate inclusions (CIs). In the present study, we re-evaluated this autopsied patient (proband) with further immunohistochemical observation as well as mutational analysis of the superoxide dismutase 1 (SOD1) gene. A review of the clinical features of the proband's family revealed five affected members (including the proband) over two successive generations who showed marked variability in clinical presentation, such as the age at onset. The proband was found to harbor a heterozygous missense mutation in exon 4 (I104F) of the SOD1 gene. In the brain and spinal cord, SOD1-positive neuronal cytoplasmic inclusions (NCIs) were found to be more widely distributed than CIs, the latter being weakly positive for SOD1. No Lewy body-like hyaline inclusions were found. This is considered to be the first description of an autopsy case of FALS with an I104F SOD1 gene mutation, suggesting that combination of marked intra-familial clinical variability and multisystem degeneration with occurrence of CIs and SOD1-positive NCIs is a characteristic feature of FALS with this SOD1 gene mutation.

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  • Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats 査読

    Masato Kanazawa, Minami Miura, Masafumi Toriyabe, Misaki Koyama, Masahiro Hatakeyama, Masanori Ishikawa, Takashi Nakajima, Osamu Onodera, Tetsuya Takahashi, Masatoyo Nishizawa, Takayoshi Shimohata

    SCIENTIFIC REPORTS7   42582   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-beta polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

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  • Characteristic Brain MRI Features of Manifesting Heterozygotes With Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

    Masahiro Uemura, Hiroaki Nozaki, Yumi Sekine, Ikuko Mizuta, Tomoko Noda, Kazuhide Miyazaki, Muichi Kaito, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Kiyomi Yamane, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Toshiki Mizuno, Masatoyo Nishizawa, Osamu Onodera

    STROKE48   2017年2月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

    T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    European Journal of Neurology24 ( 1 ) 37 - 45   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

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  • Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 査読

    Masahiro Uemura, Hiroaki Nozaki, Osamu Onodera

    Brain and Nerve69 ( 1 ) 25 - 33   2017年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Igaku-Shoin Ltd  

    Cerebral small vessel disease (CSVD) is frequently observed among the elderly and is known to cause dementia and gait disturbance associated with white matter lesions, lacunar infarcts, and cerebral hemorrhage. Molecular mechanistic studies promise to provide new insights into the pathogenesis of hereditary CSVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is one of the hereditary CSVDs caused by a mutation in the hightemperature requirement serine peptidase A1 (HTRA1) gene. The loss of HTRA1 protease activity increases signaling via transforming growth factor (TGF)β, thereby resulting in CARASIL. Although the CARASIL has been characterized by juvenile onset alopecia and spondylosis deformans, these features are not always observed in individuals with an HTRA1 mutation. Moreover, some HTRA1 mutations cause CSVD in heterozygous states. Therefore, the clinical features of CSVD resulting from an HTRA1 mutation extend to patients with CSVD alone or to those with dominantly inherited CSVD.

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  • Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation 査読

    T. Konno, K. Yoshida, T. Mizuno, T. Kawarai, M. Tada, H. Nozaki, S. -I. Ikeda, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    EUROPEAN JOURNAL OF NEUROLOGY24 ( 1 ) 37 - 45   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.
    Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.
    Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype similar to genotype correlations.
    Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

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  • Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    T. Konno, D. F. Broderick, N. Mezaki, A. Isami, D. Kaneda, Y. Tashiro, T. Tokutake, B. M. Keegan, B. K. Woodruff, T. Miura, H. Nozaki, M. Nishizawa, O. Onodera, Z. K. Wszolek, T. Ikeuchi

    AMERICAN JOURNAL OF NEURORADIOLOGY38 ( 1 ) 77 - 83   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC NEURORADIOLOGY  

    Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.

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  • A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review 査読

    Muhammad Ibrahimi, Hiroaki Nozaki, Angelica Lee, Osamu Onodera, Raymond Reichwein, Matthew Wicklund, Mohammad El-Ghanem

    CEREBROVASCULAR DISEASES44 ( 3-4 ) 135 - 140   2017年

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    記述言語:英語   出版者・発行元:KARGER  

    Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G&gt;A (p.Gly206Arg) in the HTRA1 gene. Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G&gt;A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. Conclusion: We discovered a novel missense mutation (c.616G&gt;A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-beta 1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included. (C) 2017 S. Karger AG, Basel

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  • Dissociation between intact vibratory sensation and impaired joint position sensation may predict ataxia of spinal origin 査読

    Masato Kanazawa, Keiichi Katsumi, Takayoshi Tokutake, Naoto Endo, Osamu Onodera, Masatoyo Nishizawa

    Interdisciplinary Neurosurgery: Advanced Techniques and Case Management6   68 - 70   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    Vibratory and joint position sensations are usually impaired simultaneously and afferents for both sensations ascend the dorsal columns. There are a few evidences that the central pathways in the spinal cord for position and vibratory sensations are not identical. In this study, we examined the clinical features of patients with sensory impairments of vibratory and joint position sensations. According to 43 evaluated patients’ results, the dissociation between an intact vibratory sensation and impaired joint position sensation may be important for the diagnosis of spinal disorders. We also report three cases of patients with spinal ataxia caused by sensory impairments and who show the dissociation between an impaired joint position sensation and an intact vibratory sensation. The combination of intact vibration sensation and impaired joint position sensation may suggest a dorsal column lesion in the spinal cord.

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    その他リンク: http://orcid.org/0000-0001-6337-8156

  • Performance of a real-time PCR-based approach and droplet digital PCR in detecting human parechovirus type 3 RNA 査読

    Yuta Aizawa, Akihide Koyama, Tomohiko Ishihara, Osamu Onodera, Akihiko Saitoh

    JOURNAL OF CLINICAL VIROLOGY84   27 - 31   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Background: Human parechovirus type 3 (HPeV3) is an emerging virus that causes sepsis and meningoencephalitis in neonates and young infants. Correct diagnosis of HPeV3 infection is critical in determining appropriate management and predicting patients' clinical course. Real-time reverse transcription PCR (RT-PCR) analysis of serum and/or cerebrospinal fluid (CSF) has been used to diagnose HPeV3 infection; however, the assay detection limits have not been fully evaluated.
    Objectives: We tested the hypothesis that droplet digital RT-PCR (RT-ddPCR) a novel technique that precisely quantitates low-copy target genes by diluting and partitioning samples into compartments increases the detection rate of HPeV3 RNA as compared with real-time RT-PCR.
    Study design: Using samples with predetermined HPeV3 copy numbers, we evaluated one-step and two-step RT-ddPCR. Then, we tested two-step RT-ddPCR and real-time RT-PCR, using clinical samples with low copy numbers. Finally, we used two-step RT-ddPCR to evaluate clinical samples obtained from HPeV3-infected patients with positive serum but negative CSF, as determined by real-time RT-PCR.
    Results: Two-step RT-ddPCR was less variable and more specific than one-step RT-ddPCR. Two-step RT-ddPCR detected HPeV3 RNA in all six CSF samples; four samples (67%) were reproducibly positive and the other two samples (33%) were positive at least once in four replicates. Finally, no nonspecific droplet was positive by two-step RT-ddPCR.
    Conclusions: Two-step RT-ddPCR may enhance the rate of HPeV3 RNA detection from samples with low viral loads, thereby improving diagnosis and management of HPeV3-infected patients. (C) 2016 Elsevier B.V. All rights reserved.

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  • Clinical Characterization of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew K. Wszolek, Takeshi Ikeuchi

    ANNALS OF NEUROLOGY80   S194 - S194   2016年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

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  • Characteristic Microglial Features in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids 査読

    Mari Tada, Takuya Konno, Masayoshi Tada, Toshiyuki Tezuka, Takeshi Miura, Naomi Mezaki, Ken-ichi Okazaki, Musashi Arakawa, Kyoko Itoh, Toru Yamamoto, Hideaki Yokoo, Nobuaki Yoshikura, Kenji Ishihara, Masao Horie, Hirohide Takebayashi, Yasuko Toyoshima, Makoto Naito, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi, Takeshi Ikeuchi, Akiyoshi Kakita

    ANNALS OF NEUROLOGY80 ( 4 ) 554 - 565   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
    Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
    Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
    Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations.

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  • Clinicopathological characteristics of patients with amyotrophic lateral sclerosis resulting in a totally locked-in state (communication Stage V) 査読

    Kentaro Hayashi, Yoko Mochizuki, Ryoko Takeuchi, Toshio Shimizu, Masahiro Nagao, Kazuhiko Watabe, Nobutaka Arai, Kiyomitsu Oyanagi, Osamu Onodera, Masaharu Hayashi, Hitoshi Takahashi, Akiyoshi Kakita, Eiji Isozaki

    ACTA NEUROPATHOLOGICA COMMUNICATIONS4 ( 1 ) 107   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI. The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients. Regardless of accumulated protein, all the patients showed common lesions in the pallido-nigro-luysian system, brainstem reticular formation, and cerebellar efferent system, in addition to motor neurons. In patients with pTDP-43-ir NCI, patients with NCI in the hippocampal dentate granule neurons (DG) showed a neuronal loss in the cerebral cortex, and patients without NCI in DG showed a preserved cerebral cortex. By contrast, in patients with FUS-ir NCI, patients with NCI in DG showed a preserved cerebral cortex and patients without NCI in DG showed marked cerebral degeneration. The cerebral cortex of patients with SOD1-ir NCI was preserved. Together, these findings suggest that lesions of the cerebrum are probably not necessary for progression to Stage V. In conclusion, patients with ALS that had progressed to result in communication Stage V showed rapidly-progressed symptoms, and their common lesions could cause the manifestations of communication Stage V.

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  • Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43 査読

    Akihide Koyama, Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Atsushi Shiga, Yasuko Toyoshima, Misaki Koyama, Takuya Konno, Sachiko Hirokawa, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    NUCLEIC ACIDS RESEARCH44 ( 12 ) 5820 - 5836   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

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  • Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes 査読

    Ryoko Takeuchi, Mari Tada, Atsushi Shiga, Yasuko Toyoshima, Takuya Konno, Tomoe Sato, Hiroaki Nozaki, Taisuke Kato, Masao Horie, Hiroshi Shimizu, Hirohide Takebayashi, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA COMMUNICATIONS4 ( 1 ) 61   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

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  • Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. 査読 国際誌

    Hiroaki Nozaki, Taisuke Kato, Megumi Nihonmatsu, Yohei Saito, Ikuko Mizuta, Tomoko Noda, Ryoko Koike, Kazuhide Miyazaki, Muichi Kaito, Shoichi Ito, Masahiro Makino, Akihide Koyama, Atsushi Shiga, Masahiro Uemura, Yumi Sekine, Ayuka Murakami, Suzuko Moritani, Kenju Hara, Akio Yokoseki, Ryozo Kuwano, Naoto Endo, Takeshi Momotsu, Mari Yoshida, Masatoyo Nishizawa, Toshiki Mizuno, Osamu Onodera

    Neurology86 ( 21 ) 1964 - 74   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

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  • Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL 査読

    Hiroaki Nozaki, Taisuke Kato, Megumi Nihonmatsu, Yohei Saito, Ikuko Mizuta, Tomoko Noda, Ryoko Koike, Kazuhide Miyazaki, Muichi Kaito, Shoichi Ito, Masahiro Makino, Akihide Koyama, Atsushi Shiga, Masahiro Uemura, Yumi Sekine, Ayuka Murakami, Suzuko Moritani, Kenju Hara, Akio Yokoseki, Ryozo Kuwano, Naoto Endo, Takeshi Momotsu, Mari Yoshida, Masatoyo Nishizawa, Toshiki Mizuno, Osamu Onodera

    NEUROLOGY86 ( 21 ) 1964 - 1974   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective:To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals.Methods:We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography.Results:We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation.Conclusions:The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

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  • Proposed Diagnostic Criteria for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia 査読

    Takuya Konno, Kunihiro Yoshida, Toshiki Mizuno, Toshitaka Kawarai, Masayoshi Tada, Hiroaki Nozaki, Shu-Ichi Ikeda, Masatoyo Nishizawa, Osamu Onodera, Zbigniew Wszolek, Takeshi Ikeuchi

    NEUROLOGY86   2016年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias 査読

    Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

    NEUROCHEMISTRY INTERNATIONAL94   1 - 8   2016年3月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Modulation of the intracellular calcium concentration is a ubiquitous signaling system involved in the control of numerous biological processes in a wide variety of cells. Inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs), which act as calcium release channels in the ER membrane, play a key role in the regulation of intracellular calcium concentration. IP3R type 1 (IP(3)R1) is the major neuronal IP3R isoform in the central nervous system and particularly abundant in cerebellar Purkinje cells. Heterozygous deletions or missense mutations in ITPR1, which encodes IP(3)R1, result in autosomal dominantly inherited spinocerebellar ataxias (SCAs), including SCA types 15 (SCA15) and 29 (SCA29). In addition, homozygous missense mutations in carbonic anhydrase-related protein VIII (CARP), which suppresses the ability of IP3 to bind to IP(3)R1, cause a recessively inherited ataxia with mild cognitive impairment with/without quadrupedal gait. Moreover, cytosolic calcium overload with excessive IP(3)R1 activity has been implicated in the pathogenesis of other SCAs, including SCA types 2 (SCA2) and 3 (SCA3). These facts indicate that dysregulation of IP3R-mediated calcium signaling is linked to the pathogenesis of SCAs. Here, we focus on the molecular basis of SCA15 and SCA29, which are caused by mutations in ITPR1. In addition, we discuss other SCAs whose pathogenesis may be linked to aberrant activation of IP3R-mediated Ca2+ signaling. (C) 2016 Elsevier Ltd. All rights reserved.

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  • Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology 査読

    Yuichi Yokoyama, Yasuko Toyoshima, Atsushi Shiga, Mari Tada, Hideaki Kitamura, Kazuko Hasegawa, Osamu Onodera, Takeshi Ikeuchi, Toshiyuki Someya, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    BRAIN PATHOLOGY26 ( 2 ) 155 - 166   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n=9) and Type 2 (n=9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLAType 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at approximate to 35kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

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  • Modifiable Factors Associated with Cognitive Impairment in 1,143 Japanese Outpatients: The Project in Sado for Total Health (PROST) 査読

    Kaori Kitamura, Yumi Watanabe, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

    Dementia and Geriatric Cognitive Disorders Extra6 ( 2 ) 341 - 349   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:S. Karger AG  

    Background/Aims: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population. Methods: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score &lt
    24) as an outcome. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) for cognitive impairment. Results: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p &lt
    0.001), low BMI (&lt
    21.1
    OR 1.39, 95% CI 1.12-1.72), a history of stroke (p = 0.003), a history of myocardial infarction (p = 0.038), low fruit consumption (p for trend = 0.012), and low green tea consumption (p for trend = 0.032) were independently associated with a higher prevalence of cognitive impairment. Conclusions: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.

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  • Elevated C-Reactive Protein Is Associated with Cognitive Decline in Outpatients of a General Hospital: The Project in Sado for Total Health (PROST) 査読

    Yumi Watanabe, Kaori Kitamura, Kazutoshi Nakamura, Kazuhiro Sanpei, Minako Wakasugi, Akio Yokoseki, Osamu Onodera, Takeshi Ikeuchi, Ryozo Kuwano, Takeshi Momotsu, Ichiei Narita, Naoto Endo

    DEMENTIA AND GERIATRIC COGNITIVE DISORDERS EXTRA6 ( 1 ) 10 - 19   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background/Aims: We aimed to determine whether the concentration of serum C-reactive protein (CRP) is associated with cognitive function in an adult Japanese population. Methods: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST; n = 454; mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score <24 were considered 'cognitively declined'. Concentrations of serum high-sensitivity CRP were measured. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for cognitive decline, adjusting for the covariates of age, sex, BMI, disease history, and APOE allele. Results: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women. Conclusion: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women. (C) 2016 The Author(s) Published by S. Karger AG, Basel

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  • Characteristic features and progression of abnormalities on MRI for CARASIL 査読

    Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Masatoyo Nishizawa, Osamu Onodera

    NEUROLOGY85 ( 5 ) 459 - 463   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives:The objective of this study was to clarify the characteristic brain MRI findings for genetically diagnosed CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy).Methods:Seven patients with CARASIL carrying HTRA1 mutations (representing 6 Japanese families) were included in this study. Eighteen brain MRIs were reviewed and evaluated with a new rating scale based on scoring for abnormal hyperintense lesions and atrophy.Results:At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami. Patients with longer time from the onset of cognitive impairment had higher MRI severity score. The atrophy advanced, followed by white matter lesion progression. During the early stage, hyperintense lesions were observed in the frontal white matter, external capsule, and pons. During the late stage, the arc-shaped hyperintense lesion from the pons to the middle cerebellar peduncles, which we designated the arc sign, became evident. The arc sign was a characteristic finding for CARASIL in the advanced stage.Conclusions:These characteristic MRI findings for CARASIL are useful for selecting patients for genetic testing. The rating scale correlates well with disease duration and might be useful for assessing disease progression.

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  • Redefining cerebellar ataxia in degenerative ataxias: lessons from recent research on cerebellar systems 査読

    Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY86 ( 8 ) 922 - 928   2015年8月

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    記述言語:英語   出版者・発行元:BMJ PUBLISHING GROUP  

    Recent advances in our understanding of neurophysiological functions in the cerebellar system have revealed that each region involved in degenerative ataxias contributes differently. To regulate voluntary movements, the cerebellum forms internal models within its neural circuits that mimic the behaviour of the sensorimotor system and objects in the external environment. The cerebellum forms two different internal models: forward and inverse. The forward model is formed by efference copy signals conveyed by the corticopontocerebellar system, and it derives the estimated consequences for action. The inverse model describes sequences of motor commands to accomplish an aim. During motor learning, we improve internal models by comparing the estimated consequence of an action from the forward model with the actual consequence of the action produced by the inverse model. The functions of the cerebellum encompass the formation, storage and selection of internal models. Considering the neurophysiological properties of the cerebellar system, we have classified degenerative ataxias into four types depending on which system is involved: Purkinje cells, the corticopontocerebellar system, the spinocerebellar system and the cerebellar deep nuclei. With regard to their respective contributions to the internal models, we speculate that loss of Purkinje cells leads to malformation of the internal models, whereas disturbance of the afferent system, corticopontocerebellar system or spinocerebellar system leads to mis-selection of the proper internal model. An understanding of the pathophysiological properties of ataxias in each degenerative ataxia enables the development of new methods to evaluate ataxias.

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  • Variants associated with Gaucher disease in multiple system atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Duerr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B. Stern, Virginia M. -Y. Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J. Ozelius, Tatiana Foroud, Shoji Tsuji

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY2 ( 4 ) 417 - 426   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

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  • Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (vol 45, pg 3447, 2014) 査読

    Nozaki

    STROKE45 ( 11 ) E237 - E237   2014年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1161/STR.0000000000000044

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  • C9ORF72 repeat-associated non-ATG-translated polypeptides are distributed independently of TDP-43 in a Japanese patient with c9ALS 査読

    T. Konno, M. Tada, A. Shiga, A. Tsujino, H. Eguchi, M. Masuda-Suzukake, M. Hasegawa, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY40 ( 6 ) 783 - 788   2014年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    DOI: 10.1111/nan.12157

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  • A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease 査読

    Gen Tamiya, Satoshi Makino, Makiko Hayashi, Akiko Abe, Chikahiko Numakura, Masao Ueki, Atsushi Tanaka, Chizuru Ito, Kiyotaka Toshimori, Nobuhiro Ogawa, Tomoya Terashima, Hiroshi Maegawa, Daijiro Yanagisawa, Ikuo Tooyama, Masayoshi Tada, Osamu Onodera, Kiyoshi Hayasaka

    AMERICAN JOURNAL OF HUMAN GENETICS95 ( 3 ) 294 - 300   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6de1CACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.

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  • Bunina bodies in motor and non-motor neurons revisited: A pathological study of an ALS patient after long-term survival on a respirator 査読

    Tadashi Kimura, Haishan Jiang, Takuya Konno, Makiko Seto, Keisuke Iwanaga, Mitsuhiro Tsujihata, Akira Satoh, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY34 ( 4 ) 392 - 397   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Bunina bodies (BBs) are small eosinophilic neuronal cytoplasmic inclusions (NCIs) found in the remaining lower motor neurons (LMNs) of patients with sporadic amyotrophic lateral sclerosis (SALS), being a specific feature of the cellular pathology. We examined a case of SALS, unassociated with TDP-43 or C9ORF72 mutation, of 12 years duration in a 75-year-old man, who had received artificial respiratory support for 9 years, and showed widespread multisystem degeneration with TDP-43 pathology. Interestingly, in this patient, many NCIs reminiscent of BBs were observed in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus. As BBs in the cerebellar dentate nucleus have not been previously described, we performed ultrastructural and immunohistochemical studies of these NCIs to gain further insight into the nature of BBs. In each region, the ultrastructural features of these NCIs were shown to be identical to those of BBs previously described in LMNs. These three regions and the relatively well preserved sacral anterior horns (S1 and S2) and facial motor nucleus were immunostained with antibodies against cystatin C (CC) and TDP-43. Importantly, it was revealed that BBs exhibiting immunoreactivity for CC were a feature of LMNs, but not of non-motor neurons, and that in the cerebellar dentate nucleus, the ratio of neurons with BBs and TDP-43 inclusions/neurons with BBs was significantly lower than in other regions. These findings suggest that the occurrence of BBs with CC immunoreactivity is intrinsically associated with the particular cellular properties of LMNs, and that the mechanism responsible for the formation of BBs is distinct from that for TDP-43 inclusions.

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  • Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations 査読

    Y. -J. Fu, I. Aida, M. Tada, M. Tada, Y. Toyoshima, S. Takeda, T. Nakajima, H. Naito, M. Nishizawa, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY40 ( 5 ) 551 - 563   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Aims: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. Methods: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. Results: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. Conclusions: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.

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  • A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan 査読

    Kenichi Yasui, Ichiro Yabe, Kunihiro Yoshida, Kazuaki Kanai, Kimihito Arai, Mizuki Ito, Osamu Onodera, Shigeru Koyano, Eiji Isozaki, Setsu Sawai, Yoshiki Adachi, Hidenao Sasaki, Satoshi Kuwabara, Takamichi Hattori, Gen Sobue, Hidehiro Mizusawa, Shoji Tsuji, Masatoyo Nishizawa, Kenji Nakashima

    ORPHANET JOURNAL OF RARE DISEASES9   118   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression.Methods: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits.Results: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 +/- 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease.Conclusions: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 +/- 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

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  • A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories 査読

    Chizuru Akimoto, Alexander E. Volk, Marka van Blitterswijk, Marleen Van den Broeck, Claire S. Leblond, Serge Lumbroso, William Camu, Birgit Neitzel, Osamu Onodera, Wouter van Rheenen, Susana Pinto, Markus Weber, Bradley Smith, Melanie Proven, Kevin Talbot, Pamela Keagle, Alessandra Chesi, Antonia Ratti, Julie van der Zee, Helena Alstermark, Anna Birve, Daniela Calini, Angelica Nordin, Daniela C. Tradowsky, Walter Just, Hussein Daoud, Sabrina Angerbauer, Mariely DeJesus-Hernandez, Takuya Konno, Anjali Lloyd-Jani, Mamede de Carvalho, Kevin Mouzat, John E. Landers, Jan H. Veldink, Vincenzo Silani, Aaron D. Gitler, Christopher E. Shaw, Guy A. Rouleau, Leonard H. van den Berg, Christine Van Broeckhoven, Rosa Rademakers, Peter M. Andersen, Christian Kubisch

    JOURNAL OF MEDICAL GENETICS51 ( 6 ) 419 - 424   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories.
    Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference.
    Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories.
    Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

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  • Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases 査読

    Osamu Onodera, Tomohiko Ishihara, Atsushi Shiga, Yuko Ariizumi, Akio Yokoseki, Masatoyo Nishizawa

    NEUROPATHOLOGY34 ( 1 ) 99 - 107   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate-rich (U) snRNAs (small nuclear RNAs) and protein complex, small nuclear ribonuclearprotein (snRNP). Spliceosomes regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre-mRNA splicing. Although the major class of spliceosomes regulates most pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre-mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.

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  • IP3 receptors in neurodegenerative disorders: Spinocerebellar ataxias and Huntington’s and Alzheimer’s diseases 査読

    Masayoshi Tada, Masatoyo Nishizawa, Osamu Onodera

    Pathologies of Calcium Channels   579 - 600   2014年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer Berlin Heidelberg  

    Modulation of intracellular calcium concentration is a ubiquitous signaling system involved in numerous biological processes in diverse cell types. Alterations of intracellular calcium homeostasis have been implicated in age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and spinocerebellar ataxias (SCAs). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), calcium release channels in the ER membrane, play a key role in regulating intracellular calcium concentration. IP3R type 1 (IP3R1), a major neuronal type of IR3R, is expressed ubiquitously and is involved in diverse biological processes. Cerebellar Purkinje cells are mainly affected by alterations in IP3R1. Heterozygous deletion or missense mutations in ITPR1, the IP3R1 gene, result in autosomal dominantly inherited ataxias, including SCA type 15 or 29. In addition, mutations in carbonic anhydrase-related protein VIII, which suppresses the binding ability of IP3to IP3R1, cause recessively, inherited ataxia. These results indicate that IP3R1-mediated calcium signaling has an important role in maintaining the function of Purkinje cells. Moreover, cytosolic calcium overload with excessive IP3R1 activity has been implicated in pathogenesis of other neurodegenerative diseases, including SCA type 2, SCA type 3, Huntington’s disease, and Alzheimer’s disease, where dysregulation of IP3R1-mediated calcium signaling may link to the pathogenesis.

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  • Haploinsufficiency of CSF-1R and clinicopathologic characterization in patients with HDLS 査読

    Takuya Konno, Masayoshi Tada, Mari Tada, Akihide Koyama, Hiroaki Nozaki, Yasuo Harigaya, Jin Nishimiya, Akiko Matsunaga, Nobuaki Yoshikura, Kenji Ishihara, Musashi Arakawa, Aiko Isami, Kenichi Okazaki, Hideaki Yokoo, Kyoko Itoh, Makoto Yoneda, Mitsuru Kawamura, Takashi Inuzuka, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Akiyoshi Kakita, Takeshi Ikeuchi

    NEUROLOGY82 ( 2 ) 139 - 148   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective:To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation.Methods:We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically.Results:We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution.Conclusions:These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

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  • Aberration of the spliceosome in amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa

    Clinical Neurology54 ( 12 ) 1155 - 1157   2014年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:Societas Neurologica Japonica  

    TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA.

    DOI: 10.5692/clinicalneurol.54.1155

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  • Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia 査読

    Masato Kanazawa, Mari Tada, Osamu Onodera, Hitoshi Takahashi, Masatoyo Nishizawa, Takayoshi Shimohata

    PARKINSONISM & RELATED DISORDERS19 ( 12 ) 1149 - 1151   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Background: Patients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course.
    Methods: We reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset.
    Results: The age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035).
    Conclusions: Older onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia. (C) 2013 Elsevier Ltd. All rights reserved.

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  • ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19 査読

    Yuji Takahashi, Yoko Fukuda, Jun Yoshimura, Atsushi Toyoda, Kari Kurppa, Hiroyoko Moritoyo, Veronique V. Belzil, Patrick A. Dion, Koichiro Higasa, Koichiro Doi, Hiroyuki Ishiura, Jun Mitsui, Hidetoshi Date, Budrul Ahsan, Takashi Matsukawa, Yaeko Ichikawa, Takashi Moritoyo, Mayumi Ikoma, Tsukasa Hashimoto, Fumiharu Kimura, Shigeo Murayama, Osamu Onodera, Masatoyo Nishizawa, Mari Yoshida, Naoki Atsuta, Gen Sobue, Jennifer A. Fifita, Kelly L. Williams, Ian P. Blair, Garth A. Nicholson, Paloma Gonzalez-Perez, Robert H. Brown, Masahiro Nomoto, Klaus Elenius, Guy A. Rouleau, Asao Fujiyama, Shinichi Morishita, Jun Goto, Shoji Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS93 ( 5 ) 900 - 905   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (PALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G&gt;A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C&gt;T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.

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  • Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    HUMAN MOLECULAR GENETICS22 ( 20 ) 4136 - 4147   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.

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  • Patient with insidious hypoactive delirium associated with pregabalin 査読

    Naomi Mezaki, Tomohiko Ishihara, Tetsutaro Ozawa, Ryoko Takeuchi, Osamu Onodera, Takayoshi Shimohata, Masatoyo Nishizawa

    Neurology and Clinical Neuroscience (Online Early View)   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene 査読

    Hiroshi Shimizu, Yasuko Toyoshima, Atsushi Shiga, Akio Yokoseki, Keiko Arakawa, Yumi Sekine, Takayoshi Shimohata, Takeshi Ikeuchi, Masatoyo Nishizawa, Akiyoshi Kakita, Osamu Onodera, Hitoshi Takahashi

    Acta Neuropathologica126 ( 3 ) 453 - 459   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulating evidence suggests that heterozygous mutations in the SQSTM1 gene, which encodes p62 protein, are associated with amyotrophic lateral sclerosis (ALS). Here, we report a Japanese patient with sporadic, late-onset ALS who harbored compound heterozygous SQSTM1 mutations (p.[Val90Met]
    [Val153Ile]). Autopsy examination revealed that although TDP-43 pathology was rather widespread, the selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in the lower motor neurons (LMNs) was a characteristic feature. No Bunina bodies were found. Ultrastructurally, p62-positive cytoplasmic inclusions observed in the spinal anterior horn cells were composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures. Another feature of interest was concomitant Lewy body pathology. The occurrence of distinct p62 pathology in the LMNs in this patient indicates the pathogenic role of SQSTM1 mutations in the development of a subset of ALS. © 2013 Springer-Verlag Berlin Heidelberg.

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  • Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity 査読

    Fusako Usuki, Akio Yamashita, Tadafumi Shiraishi, Atsushi Shiga, Osamu Onodera, Itsuro Higuchi, Shigeo Ohno

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA110 ( 37 ) 15037 - 15042   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI a 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cell-cycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases.

    DOI: 10.1073/pnas.1300654110

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  • Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy 査読

    Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Yoko Fukuda, Yaeko Ichikawa, Hidetoshi Date, Budrul Ahsan, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Atsushi Iwata, Jun Goto, Yorihiro Yamamoto, Makiko Komata, Katsuhiko Shirahige, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hiroshi Takashima, Ryozo Kuwano, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Hiroyuki Soma, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alexandra Duerr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Clifford W. Shults, Caroline M. Tanner, Walter A. Kukull, Virginia M. -Y. Lee, Eliezer Masliah, Phillip A. Low, Paola Sandroni, John Q. Trojanowski, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

    NEW ENGLAND JOURNAL OF MEDICINE369 ( 3 ) 233 - 244   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MASSACHUSETTS MEDICAL SOC  

    Background
    Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.
    Methods
    In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q(10). Levels of coenzyme Q(10) in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.
    Results
    We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.
    Conclusions
    Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)
    Multiple-system atrophy is a rare neurodegenerative disease characterized by autonomic failure. Mutations affecting an enzyme essential for the synthesis of coenzyme Q10 confer susceptibility to the disease in some persons.

    DOI: 10.1056/NEJMoa1212115

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  • [Hereditary cerebral small-vessel disease]. 査読

    Nozaki H, Nishizawa M, Onodera O

    Nihon rinsho. Japanese journal of clinical medicine71 ( 3 ) 545 - 554   2013年3月

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  • Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): Clinical Characteristics and Molecular Analyses of CSF-1R 査読

    Konno Takuya, Tada Masayoshi, Koyama Akihide, Tada Mari, Sugai Akihiro, Nozaki Hiroaki, Matsunaga Akiko, Harigaya Yasuo, Nishimiya Jin, Ishihara Kenji, Yoneda Makoto, Kakita Akiyoshi, Takahashi Hitoshi, Kawamura Mitsuru, Onodera Osamu, Nishizawa Masatoyo, Ikeuchi Takeshi

    NEUROLOGY80   2013年2月

  • MRI Features of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

    Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Mamoru Shibata, Shimoe Yutaka, Akiko Shirata, Sohei Yanagawa, Mikio Hirayama, Kiyomi Yamane, Imaharu Nakano, Norihiro Suzuki, Masatoyo Nishizawa, Osamu Onodera

    NEUROLOGY80   560 - 566   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Early Clinical Features in Japanese Patients with Pathologically Proven Progressive Supranuclear Palsy with Cerebellar Ataxia 査読

    Masato Kanazawa, Takayoshi Shimohata, Mari Tada, Osamu Onodera, Hitoshi Takahashi, Masatoyo Nishizawa

    NEUROLOGY80   2013年2月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1016/j.parkreldis.2013.07.019

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  • Molecular pathogenesis of ALS in TDP43 era 査読

    Osamu Onodera

    Clinical Neurology53 ( 11 ) 1077 - 1079   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    To clarify the molecular pathogenesis of amyotrophic lateral sclerosis (ALS) associated with TAR-DNA binding protein 43?kDd (TDP-43), the quality and quantity of TDP-43 take a crucial role. Regarding to the quality of TDP-43, TDP-43 has been reported as an aggregate-prone protein. Especially the C-terminus of the TDP-43 tends to form aggregate and has prion-like domain. Interestingly the mutations in the genes, which produce proteins with prion-like domain, have been identified in several neurodegenerative disorders. These results suggest the existence of the common property in the causative proteins for neurodegenerative disorders. For the quantity of TDP-43, the adequate amount of TDP-43 is necessary for maintaining cell function and cell survival. The amount of TDP-43 is tightly regulated by TDP-43. However the mechanism for autoregulation has not been fully elucidated. For the function of TDP-43, TDP-43 locates at stress granule, GEM and associates with the large genes and introns. Thus the alteration of TDP-43 may affect the function of stress granule, GEM and RNA metabolism in several genes. Moreover a U12 type spliceosome, which is matured in GEM, is decreased in ALS. The investigation of whether these dysfunctions explain the selective pathology in ALS provides a new therapeutic strategy for ALS.

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  • Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72 査読

    Takuya Konno, Atsushi Shiga, Akira Tsujino, Akihiro Sugai, Taisuke Kato, Kazuaki Kanai, Akio Yokoseki, Hiroto Eguchi, Satoshi Kuwabara, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    Journal of Neurology, Neurosurgery and Psychiatry84 ( 4 ) 398 - 401   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ Publishing Group  

    Background A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. Results We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. Conclusions C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

    DOI: 10.1136/jnnp-2012-302272

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  • Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 査読

    Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    PLOS ONE7 ( 8 ) e43120   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.

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  • Primary lateral sclerosis: Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration - immunohistochemical and biochemical analyses of TDP-43 査読

    Takayuki Kosaka, Yong-Juan Fu, Atsushi Shiga, Haruka Ishidaira, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    NEUROPATHOLOGY32 ( 4 ) 373 - 384   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of similar to 25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.

    DOI: 10.1111/j.1440-1789.2011.01271.x

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  • Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene deletion, the mutation for spinocerebellar ataxia type 15, in Japan screened by gene dosage 査読

    Masato Obayashi, Kinya Ishikawa, Yuishin Izumi, Makoto Takahashi, Yusuke Niimi, Nozomu Sato, Osamu Onodera, Ryuji Kaji, Masatoyo Nishizawa, Hidehiro Mizusawa

    JOURNAL OF HUMAN GENETICS57 ( 3 ) 202 - 206   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Spinocerebellar ataxia type 15 (SCA15) is an autosomal dominant neurodegenerative disorder clinically characterized by late-onset, slowly progressive pure cerebellar ataxia. This disease is caused by a heterozygous deletion of the inositol 1, 4, 5-triphosphate receptor type 1 (ITPR1) gene, suggesting that haploinsufficiency of the receptor function is the plausible disease mechanism. To clarify the prevalence of SCA15 in Japan, we designed four sets of probes and primers in different regions of ITPR1 and performed TaqMan PCR assay to search for gene deletions in 226 index SCA patients excluded for repeat expansion disorders. Deletion was found in only one patient, in whom gait ataxia started at 51 years of age and progressed to show cerebellar ataxia. This study demonstrates a simple but efficient method for screening ITPR1 deletion. We also conclude that ITPR1 gene deletions are much rare in Japan than in Europe, comprising only 0.3% in all SCAs in Japan. Journal of Human Genetics (2012) 57, 202-206; doi:10.1038/jhg.2012.5; published online 9 February 2012

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  • Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis 査読

    K. Soma, Y. -J. Fu, K. Wakabayashi, O. Onodera, A. Kakita, H. Takahashi

    NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY38 ( 1 ) 54 - 60   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    K. Soma, Y.-J. Fu, K. Wakabayashi, O. Onodera, A. Kakita and H. Takahashi (2012) Neuropathology and Applied Neurobiology38, 5460

    DOI: 10.1111/j.1365-2990.2011.01175.x

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  • What is ataxia? - Towards developing a new scale for ataxia 査読

    Osamu Onodera

    Clinical Neurology52 ( 11 ) 988 - 989   2012年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    The molecular mechanism for ataxias has been elucidated in past 20 years. However, still it has not been developed a effective drug which prevents the disease progression or improves their symptom. One of the reasons for that is that the scales for ataxias, which we are using, are not suitable for clinical trial. The number of participant and the duration for a clinical trial is determined by the sensitivity and stability of scale to evaluate the efficacy the therapeutic methods. The available scale for ataxias needs more than 100 participants to evaluation the efficacy in more than 80% power. In addition, most of the scales for ataxias are a categorized scale, which is less sensitive and stable than a continuous scale. For success for clinical trial, we have to develop a new continuous scale for ataxias. In this symposium, we will learn the recent advance of physiological role of cerebellum and imagine a new continuous scale for evaluation for ataxias.

    DOI: 10.5692/clinicalneurol.52.988

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  • Difference in MSA Phenotype Distribution Between Populations: Genetics or Environment? 査読

    Tetsutaro Ozawa, Tamas Revesz, Dominic Paviour, Andrew J. Lees, Niall Quinn, Mari Tada, Akiyoshi Kakita, Osamu Onodera, Koichi Wakabayashi, Hitoshi Takahashi, Masatoyo Nishizawa, Janice L. Holton

    JOURNAL OF PARKINSONS DISEASE2 ( 1 ) 7 - 18   2012年

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    記述言語:英語   出版者・発行元:IOS PRESS  

    The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA-P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations.

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  • [Dementia: progress in diagnosis and treatment; Topics, V. Recent topics; 4. Detection of novel dementia-related genes; 2) Dysregulation of TGF-beta family signaling and hereditary cerebral small vessel disease: insight into molecular pathogenesis of CARA 査読

    Nozaki H, Nishizawa M, Onodera O

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine100 ( 8 ) 2207 - 2213   2011年8月

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  • Neuroaxonal integrity evaluated by MR spectroscopy in a case of CARASIL 査読

    Yoshinori Nishimoto, Mamoru Shibata, Osamu Onodera, Norihiro Suzuki

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY82 ( 8 ) 860 - 861   2011年8月

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    記述言語:英語   出版者・発行元:B M J PUBLISHING GROUP  

    DOI: 10.1136/jnnp.2010.240051

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  • Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family 査読

    Haruka Yamazaki, Hiroaki Nozaki, Osamu Onodera, Takayuki Michikawa, Masatoyo Nishizawa, Katsuhiko Mikoshiba

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS410 ( 4 ) 754 - 758   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Spinocerebellar ataxia type 15 (SCA15) is a group of human neurodegenerative disorders characterized by a slowly progressing pure cerebellar ataxia. The inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP(3)R1) is an intracellular IP3-induced Ca2+ release channel that was recently identified as a causative gene for SCA15. In most case studies, a heterozygous deletion of the IP(3)R1 gene was identified. However, one Japanese SCA15 family was found to have a Pro to Leu (P1059L) substitution in IP(3)R1. To investigate the effect of the P1059L mutation, we analyzed the channel properties of the mutant human IP(3)R1 by expressing it in an IP3R-deficient B lymphocyte cell line. The P1059L mutant was a functional Ca2+ release channel with a twofold higher IP3 binding affinity compared to wild-type IP(3)R1. The cooperative dependence of the Ca2+ release activity of the mutant on IP3 concentration was reduced, but both wild-type and mutant receptors produced similar B cell receptor-induced Ca2+ signals. These results demonstrate that the Ca2+ release properties of IP(3)R1 are largely unaffected by the P1059L mutation. (C) 2011 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2011.06.043

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  • What is cerebral small vessel disease? 査読

    Osamu Onodera

    Clinical Neurology51 ( 6 ) 399 - 405   2011年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    An accumulating amount of evidence suggests that the white matter hyperintensities on T2 weighted brain magnetic resonance imaging predict an increased risk of dementia and gait disturbance. This state has been proposed as cerebral small vessel disease, including leukoaraiosis, Binswanger's disease, lacunar stroke and cerebral microbleeds. However, the concept of cerebral small vessel disease is still obscure. To understand the cerebral small vessel disease, the precise structure and function of cerebral small vessels must be clarified. Cerebral small vessels include several different arteries which have different anatomical structures and functions. Important functions of the cerebral small vessels are blood-brain barrier and perivasucular drainage of interstitial fluid from the brain parenchyma. Cerebral capillaries and glial endfeet, take an important role for these functions. However, the previous pathological investigations on cerebral small vessels have focused on larger arteries than capillaries. Therefore little is known about the pathology of capillaries in small vessel disease. The recent discoveries of genes which cause the cerebral small vessel disease indicate that the cerebral small vessel diseases are caused by a distinct molecular mechanism. One of the pathological findings in hereditary cerebral small vessel disease is the loss of smooth muscle cells, which is an also well-recognized finding in sporadic cerebral small vessel disease. Since pericytes have similar character with the smooth muscle cells, the pericytes should be investigated in these disorders. In addition, the loss of smooth muscle cells may result in dysfunction of drainage of interstitial fluid from capillaries. The precise correlation between the loss of smooth muscle cells and white matter disease is still unknown. However, the function that is specific to cerebral small vessel may be associated with the pathogenesis of cerebral small vessel disease.

    DOI: 10.5692/clinicalneurol.51.399

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  • Reduced bowel sounds in Parkinson&apos;s disease and multiple system atrophy patients 査読

    Tetsutaro Ozawa, Etsuji Saji, Ryuji Yajima, Osamu Onodera, Masatoyo Nishizawa

    CLINICAL AUTONOMIC RESEARCH21 ( 3 ) 181 - 184   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER HEIDELBERG  

    Digital auscultation of bowel sounds was performed in newly diagnosed, drug-na &lt; ve patients with Parkinson&apos;s disease (PD) (n = 10), multiple system atrophy (MSA) (n = 12), progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) (n = 7), and control subjects (n = 18). The number of bowel sounds per minute and the integrated time of bowel sounds were significantly lower in PD and MSA patients than in control subjects. Reduced bowel sounds may herald compromised gastrointestinal motility in patients with PD and MSA.

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  • Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia 査読

    Akio Yokoseki, Tomohiko Ishihara, Akihide Koyama, Atsushi Shiga, Mitsunori Yamada, Chieko Suzuki, Yoshiki Sekijima, Kyoko Maruta, Miyuki Tsuchiya, Hidetoshi Date, Tatsuya Sato, Masayoshi Tada, Takeshi Ikeuchi, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    BRAIN134 ( Pt 5 ) 1387 - 1399   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene. We previously reported that patients with frameshift mutations exhibit a more severe phenotype than those with missense mutations. However, reports on genotype-phenotype correlation in early onset ataxia with ocular motor apraxia and hypoalbuminaemia are controversial. To clarify this issue, we studied 58 patients from 39 Japanese families, including 40 patients homozygous for c.689_690insT and nine patients homozygous or compound heterozygous for p.Pro206Leu or p.Val263Gly mutations who were compared with regard to clinical phenotype. We performed Kaplan-Meier analysis and log-rank tests for the ages of onset of gait disturbance and the inability to walk without assistance. The cumulative rate of gait disturbance was lower among patients with p.Pro206Leu or p.Val263Gly mutations than among those homozygous for the c.689_690insT mutation (P = 0.001). The cumulative rate of inability to walk without assistance was higher in patients homozygous for the c.689_690insT mutation than in those with p.Pro206Leu or p.Val263Gly mutations (P = 0.004). Using a Cox proportional hazards model, we found that the homozygous c.689_690insT mutation was associated with an increased risk for onset of gait disturbance (adjusted hazard ratio: 6.60) and for the inability to walk without assistance (adjusted hazard ratio: 2.99). All patients homozygous for the c.689_690insT mutation presented ocular motor apraxia at < 15 years of age. Approximately half the patients homozygous for the c.689_690insT mutation developed cognitive impairment. In contrast, in the patients with p.Pro206Leu or p.Val263Gly mutations, only similar to 50% of the patients exhibited ocular motor apraxia and they never developed cognitive impairment. The stepwise multivariate regression analysis using sex, age and the number of c.689_690insT alleles as independent variables revealed that the number of c.689_690insT alleles was independently and negatively correlated with median motor nerve conduction velocities, ulnar motor nerve conduction velocities and values of serum albumin. In the patient with c.[689_690insT]+[840delT], p.[Pro206Leu]+[Pro206Leu] and p.[Pro206Leu]+[Val263Gly] mutations, aprataxin proteins were not detected by an antibody to the N-terminus of aprataxin. Furthermore Pro206Leu and Val263Gly aprataxin proteins are unstable. However, the amount of the 689_690insT aprataxin messenger RNA was also decreased, resulting in more dramatic reduction in the amount of aprataxin protein from the c.689_690insT allele. In conclusion, patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation.

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  • Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1. 査読

    Shiga A, Nozaki H, Yokoseki A, Nihonmatsu M, Kawata H, Kato T, Koyama A, Arima K, Ikeda M, Katada S, Toyoshima Y, Takahashi H, Tanaka A, Nakano I, Ikeuchi T, Nishizawa M, Onodera O

    Human molecular genetics20 ( 9 ) 1800 - 1810   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/hmg/ddr063

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  • A NOVEL MUTATION IN THE HTRA1 GENE CAUSES CARASIL WITHOUT ALOPECIA 査読

    Y. Nishimoto, M. Shibata, M. Nihonmatsu, H. Nozaki, A. Shiga, A. Shirata, K. Yamane, A. Kosakai, K. Takahashi, M. Nishizawa, O. Onodera, N. Suzuki

    NEUROLOGY76 ( 15 ) 1353 - 1355   2011年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1212/WNL.0b013e318215281d

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  • Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes 査読

    Takashi Matsukawa, Muriel Asheuer, Yuji Takahashi, Jun Goto, Yasuyuki Suzuki, Nobuyuki Shimozawa, Hiroki Takano, Osamu Onodera, Masatoyo Nishizawa, Patrick Aubourg, Shoji Tsuji

    NEUROGENETICS12 ( 1 ) 41 - 50   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p = 0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.

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  • [TGF-β family signaling contributes to human cerebral small vessel disease]. 査読

    Onodera O

    Rinsho shinkeigaku = Clinical neurology51 ( 11 ) 943 - 944   2011年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    DOI: 10.5692/clinicalneurol.51.943

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  • The phenotype spectrum of Japanese multiple system atrophy 査読

    T. Ozawa, M. Tada, A. Kakita, O. Onodera, M. Tada, T. Ishihara, T. Morita, T. Shimohata, K. Wakabayashi, H. Takahashi, M. Nishizawa

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY81 ( 11 ) 1253 - 1255   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:B M J PUBLISHING GROUP  

    Objective This study aimed to determine the spectrum of pathological involvement of the striatonigral (StrN) and olivopontocerebellar (OPC) systems in Japanese patients with multiple system atrophy (MSA). This study also aimed to compare the pathological spectrum of Japanese MSA patients with the previously reported results in British MSA patients.
    Methods A semiquantitative pathological analysis of 50 MSA patients&apos; brains that were referred to the Brain Research Institute, Niigata University, Japan, was performed. The severity of neuronal cell loss was determined as previously described by the study from the Queen Square Brain Bank (QSBB), UK.
    Results The mean neuronal cell loss score was significantly higher in the OPC area than in the basal ganglia sites examined, except the dorsolateral putamen. The relative prevalence of pathological phenotypes showed that 40% of cases had OPC-predominant pathology, 18% had StrN-predominant pathology and the remaining (42%) had equivalent StrN and OPC pathology. None of the MSA cases had coexistent Lewy bodies in the dorsal motor nucleus of the vagus and the substantia nigra.
    Conclusions In contrast to the previously reported results involving British patients&apos; brains from the QSBB (OPC-predominant pathology 17%, StrN-predominant pathology 34%, equivalent StrN and OPC pathology 49%), the results of the present study showed more pathological involvement of the OPC system than of the StrN system. The rarity of Lewy bodies may underlie the phenotypic expression of Japanese MSA. The present observations reflect the disequilibrium in the phenotype distribution between the two populations.

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  • [Clinical studies on neurological disorders conducted by research consortia]. 査読

    Onodera O, Nakashima K

    Rinsho shinkeigaku = Clinical neurology50 ( 11 ) 925   2010年11月

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  • 認知症研究の新しい視点 TDP-43プロテイノパチーとしてのFTLD/ALS 査読

    石原 智彦, 有泉 優子, 志賀 篤, 横関 明男, 佐藤 達哉, 豊島 靖子, 柿田 明美, 高橋 均, 西澤 正豊, 小野寺 理

    臨床神経学50 ( 11 ) 1022 - 1024   2010年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

    DOI: 10.5692/clinicalneurol.50.1022

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  • Involvement of Onuf&apos;s nucleus in Machado-Joseph disease: a morphometric and immunohistochemical study 査読

    Hiroshi Shimizu, Mitsunori Yamada, Yasuko Toyoshima, Takeshi Ikeuchi, Osamu Onodera, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA120 ( 4 ) 439 - 448   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disease caused by an expansion of CAG repeats in the MJD1 gene, in which lower urinary tract dysfunction is known to be the most commonly encountered autonomic failure. However, it remains unclear whether Onuf&apos;s nucleus (ON), which plays major roles in the micturition reflex and voluntary continence, degenerates during the disease process. In the present study, we conducted a morphometric and immunohistochemical study of ON, together with the lateral nuclear group (LNG) of the sacral anterior horns, in seven patients with MJD. When compared with controls, the number of lower motor neurons in both ON and LNG was significantly smaller in the MJD patients, the former being inversely correlated with the size of the expanded CAG repeats. Notably, MJD patients with a large CAG-repeat expansion showed an ON-predominant pattern of neuronal loss, while in the remaining patients, ON and LNG were affected to a similar degree, or rather an LNG-predominant pattern of neuronal loss was evident. Moreover, when adjusted for age, the degree of neuronal loss in both ON and LNG was significantly correlated with the extent of expansion of the CAG repeats. In MJD, the remaining lower motor neurons in ON often exhibited ataxin-3- or 1C2-immunoreactive (ir) neuronal intranuclear inclusions, while no pTDP-43-ir neuronal cytoplasmic inclusions were present in these neurons. In conclusion, the present findings strongly suggest that neuronal loss in ON, the degree of which is highly influenced by the extent of expansion of CAG repeats, is a consistent feature in MJD.

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  • Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. 査読

    Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M, Nishihira Y, Miyashita A, Fujiwara H, Oyama T, Nogovicina A, Sukhomyasova A, Potapova S, Kuwano R, Takahashi H, Nishizawa M, Onodera O

    Journal of medical genetics47 ( 8 ) 538 - 548   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1136/jmg.2009.074815

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  • Polyglutamine Diseases: Where does Toxicity Come from? What is Toxicity? Where are We Going? 査読

    Toshiaki Takahashi, Shinichi Katada, Osamu Onodera

    JOURNAL OF MOLECULAR CELL BIOLOGY2 ( 4 ) 180 - 191   2010年8月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Although the genetic basis of polyglutamine diseases has been recognized for 20 years, their molecular basis is still unclear. We have no therapeutic strategies for these intractable neurodegenerative disorders. To adequately treat patients, we must clarify the molecular basis of polyglutamine diseases. Three main issues address their molecular pathogenesis: whether the specific structure of expanded polyglutamine diseases results in cellular toxicity; what type of dysfunction causes them; and how the toxic structure causes dysfunction, that is, the link between structure and dysfunction. For structures, expanded polyglutamine proteins undergo transformation from monomers to oligomers and inclusions. One can hypothesize that one of these structures might cause the polyglutamine disease. Although the expanded polyglutamine protein is toxic, it does not explain the selective vulnerability of specific neurons in each polyglutamine disease. The normal function of each protein, including protein-protein interaction and modification, might also be crucial for pathogenesis. For dysfunction, various molecular mechanisms have been proposed, including dysregulation of transcription, impairment of the ubiquitin-proteasome system, mitochondrial dysfunction, dysregulation of intracellular Ca2+ homeostasis, impairment of axonal transport and genotoxic stress. These hypotheses might correlate with each other. In addition, the disease pathogenesis of might not be exclusive to one particular structure or dysfunction. To develop a therapeutic strategy for patients with polyglutamine disease, identifying the most toxic structure and the earliest event in the pathogenesis is important. We review the current understanding of the toxic structure and dysfunction by expanded polyglutamine proteins and suggest directions for future studies of polyglutamine diseases.

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  • Long-Term Disability and Prognosis in Dentatorubral-Pallidoluysian Atrophy: a Correlation with CAG Repeat Length 査読

    Arika Hasegawa, Takeshi Ikeuchi, Ryoko Koike, Nae Matsubara, Miyuki Tsuchiya, Hiroaki Nozaki, Atsushi Homma, Jiro Idezuka, Masatoyo Nishizawa, Osamu Onodera

    MOVEMENT DISORDERS25 ( 11 ) 1694 - 1700   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion. Previous studies demonstrated that the onset of DRPLA is closely associated with CAG repeat length. However, the natural history of DRPLA has not yet been evaluated. We here retrospectively investigated the factors that determine the disease milestones and prognosis in 183 Japanese patients genetically diagnosed with DRPLA. We determined the age at onset, age at which each of the subsequent clinical manifestations appeared, age at becoming wheelchair-bound, and age at death. Kaplan-Meier analysis revealed that the patients with CAG repeats larger than the median length of 65 repeats developed each of the clinical features of DRPLA at a younger age than those with &lt;65 repeats. The patients became wheelchair-bound at a median age of 33 years (n = 61; range, 3-77 years) and died at a median age of 49 years (n = 23; range, 18-80 years). The ages at becoming wheelchair-bound and at death strongly correlated with the expanded CAG repeat length. Moreover, the patients with &gt;= 65 CAG repeats showed a more severe long-term disability and a poorer prognosis. In contrast, the rate of progression after the onset did not correlate with CAG repeat length. The CAG repeat length may have a considerable effect on not only the disease onset but also the disease milestones and prognosis in DRPLA patients. These effects of CAG repeat length may be relevant in designing future clinical therapeutic trials. (C) 2010 Movement Disorder Society

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  • Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity 査読

    Yong-Juan Fu, Yasushi Nishihira, Shigetoshi Kuroda, Yasuko Toyoshima, Tomohiko Ishihara, Makoto Shinozaki, Akinori Miyashita, Yue-Shan Piao, Chun-Feng Tan, Takashi Tani, Ryoko Koike, Keisuke Iwanaga, Mitsuhiro Tsujihata, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa, Akiyoshi Kakita, Takeshi Ikeuchi, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA120 ( 1 ) 21 - 32   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

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  • Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer&apos;s disease 査読

    Kensaku Kasuga, Takayoshi Tokutake, Atsushi Ishikawa, Tsuyoshi Uchiyama, Takahiko Tokuda, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY81 ( 6 ) 608 - 610   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:B M J PUBLISHING GROUP  

    Background The clinical diagnosis of dementia with Lewy bodies (DLB) is made on the basis of consensus criteria; however, the sensitivity of the criteria is relatively low. There are no generally accepted biomarkers to distinguish DLB from other dementias. Here the utility of quantification of a-synuclein, beta-amyloid42 (A beta 42) and tau in the CSF of patients with DLB, Alzheimer&apos;s disease (AD) and other dementias was examined.
    Methods 86 patients were divided into three age and sex matched groups: DLB (n=34), AD (n=31) and other dementias (n=21). Two patients with alpha-synuclein gene (SNCA) duplication were also examined. A beta and tau were quantified using an ELISA kit. A modified sandwich ELISA was developed which enables the sensitive quantification of CSF alpha-synuclein.
    Results Total and phosphorylated tau levels as well as A beta 40/42 and tau/A beta 42 ratios were significantly higher in AD patients than in patients with DLB (p&lt;0.01) and other dementias (p&lt;0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p&lt;0.05) and other dementias (p&lt;0.01). CSF alpha-synuclein level correlated with the A beta 42 level in DLB patients (p=0.01, r=0.43). Two patients with SNCA duplication exhibited relatively low levels of CSF alpha-synuclein.
    Conclusions The study suggests that reduced levels of CSF alpha-synuclein in DLB may reflect the accumulation of alpha-synuclein with Lewy pathology in the brain and that quantification of CSF alpha-synuclein helps in the differentiation of DLB from AD and other dementias in combination with A beta 42 and tau analysis.

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  • Molecular pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy 査読

    Atsushi Shiga, Hiroaki Nozaki, Masatoyo Nishizawa, Osamu Onodera

    Brain and Nerve62 ( 6 ) 595 - 599   2010年6月

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    記述言語:日本語  

    Ischemic cerebral small-vessel disease is a common disorder in the elderly. However, little is known about the molecular basis of ischemic cerebral small-vessel disease. We recently found that mutations in the HtrA serine peptidase 1 (HTRA1) gene cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). CARASIL is characterized by nonhypertensive cerebral small-vessel arteriopathy with alopecia and spondylosis. On neuropathologic examination, arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media are observed in cerebral small arteries. These pathologic findings resemble those observed in patients with nonhereditary ischemic cerebral small-vessel disease. HTRA1 belongs to the HTRA protein family, the members of which have dual activities as chaperones and serine proteases. Studies have shown that members of the HTRA family repress transforming growth factor-β (TGF-β) family signaling. We found that CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress TGF-β family signaling. Moreover, the amount of TGF-β1 was increased in the cerebral small arteries of CARASIL patients. In addition, the level of expression of ED-A fibronectin and versican, which is induced by TGF-β signaling, were accumulated in cerebral small arterial walls of a patient with CARASIL. Thus, we have concluded that the increased TGF-β signaling causes arteriopathy in CARASIL.

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  • Alzheimer&apos;s disease: Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration 査読

    Kenichi Okazaki, Yong-Juan Fu, Yasushi Nishihira, Minoru Endo, Takao Fukushima, Takeshi Ikeuchi, Kouichirou Okamoto, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

    NEUROPATHOLOGY30 ( 2 ) 140 - 148   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Alzheimer&apos;s disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy-proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8-positive neurofibrillary tangles (NFTs) and A beta-positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and A beta deposits may begin in the fronto-parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.

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  • Increased TGF-beta Signaling Underlies the Pathogenesis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) 査読

    Hiroaki Nozaki, Atushi Shiga, Hirotoshi Kawata, Kunimasa Arima, Kenju Hara, Toshio Fukutake, Akio Yokoseki, Akihide Koyama, Toshiaki Takahashi, Mari Ikeda, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Tadashi Yamamoto, Takeshi Ikeuchi, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

    NEUROLOGY74 ( 9 ) A445 - A445   2010年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • The clinical and pathological spectrum of TDP-43 associated ALS 査読

    Osamu Onodera, AMo Yokoseki, Chun-Feng Tan, Tomohiko Ishihara, Yasushi Nishiira, Yasuko Toyoshima, AMyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi

    Clinical Neurology50 ( 11 ) 940 - 942   2010年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 KDa (TDP43) immunopositive cytoplasmic inclusions have been found in glia and neurons of ALS patients. The discovery of TDP-43 mutations in ALS patients indicates a direct role of TDP43 in ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 immunopositive inclusions and Bunina bodies, are identical to those in sporadic ALS. Most of the mutations are located in the C-terminus of TDP43, which may function as a binding domain of heterogeneous nuclear ribonucleoprotein. Frontotemporal lobar degeneration: FTLD and FTLD/MND (motor neuron disease) also have TDP-43 immunopositive inclusions. These disorders have been named as TDP43 proteinopathy. However, patients with TDP-43 mutations rarely develop FTLD. Causative genes for familial FTLD and FTLD/MND are not linked to the TDP-43 gene. Thus, other factors may contribute to the TDP-43 pathology in these diseases. Further analysis is required to elucidate the molecular mechanism of ALS-10 and TDP-43 proteinopathy.

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  • Early-Onset Ataxia with Ocular Motor Apraxia and Hypoalbuminemia/Ataxia with Oculomotor Apraxia 1 査読

    Masayoshi Tada, Akio Yokoseki, Tatsuya Sato, Takao Makifuchi, Osamu Onodera

    DISEASES OF DNA REPAIR685   21 - 33   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG BERLIN  

    DNA single-strand breaks (SSBs) are non-overlapping discontinuities in strands of a DNA duplex. Significant attention has been given on the DNA SSB repair (SSBR) system in neurons, because the impairment of the SSBR causes human neurodegenerative disorders, including early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), also known as ataxia-oculomotor apraxia Type 1 (AOA1). EAOH/AOA1 is characterized by early-onset slowly progressive ataxia, ocular motor apraxia, peripheral neuropathy and hypoalbuminemia. Neuropathological examination reveals severe loss of Purkinje cells and moderate neuronal loss in the anterior horn and dorsal root ganglia. EAOH/AOA1 is caused by the mutation in the APTX gene encoding the aprataxin (APTX) protein. APTX interacts with X-ray repair cross-complementing group 1 protein, which is a scaffold protein in SSBR. In addition, APTX-defective cells show increased sensitivity to genotoxic agents, which result in SSBs. These results indicate an important role of APTX in SSBR. SSBs are usually accompanied by modified or damaged 5'- and 3'-ends at the break site. Because these modified or damaged ends are not suitable for DNA ligation, they need to be restored to conventional ends prior to subsequent repair processes. APTX restores the 5'-adenylate monophosphate, 3'-phosphates and 3'-phosphoglycolate ends. The loss of function of APTX results in the accumulation of SSBs, consequently leading to neuronal cell dysfunction and death.

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  • The implications of TDP-43 mutations in pathogenesis of amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Akio Yokoseki, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    Brain and Nerve61 ( 11 ) 1301 - 1307   2009年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 kDa (TDP-43) -positive-cytoplasmic inclusions have been found in the glia and neurons of ALS patients. TDP-43 -positive inclusions have been reported in several neurodegenerative disorders other than ALS. Therefore it is not clear whether TDP-43 plays a primary role in the pathogenesis of ALS. The discovery of TDP-43 mutations in ALS patients indicates that TDP-43 plays a pivotal role in the pathogenesis of ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 -positive inclusions and Bunina bodies, are identical to those in sporadic ALS
    these findings indicate that the study of ALS-10 may lead to a better understanding of sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain for heterogeneous nuclear ribonucleoprotein. Biochemical analyses of TDP-43 in sporadic ALS patients indicate that the TDP-43 is truncated, and the C-terminus is phosphorylated forming insoluble inclusions in the neurons and glia. In certain ALS-10 cases, missense mutated TDP-43s tend to be truncated and form inclusions. The cytotoxicity of these mutated TDP-43s has also been reported
    however, these results are still controversial. Therefore, further analysis is required to elucidate the molecular mechanism underlying the development of ALS-10.

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  • Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease 査読

    Chun-Feng Tan, Mitsunori Yamada, Yasuko Toyoshima, Akio Yokoseki, Yukari Miki, Yasuhiro Hoshi, Hiroyuki Kaneko, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA118 ( 4 ) 553 - 560   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at similar to 23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.

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  • Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease 査読

    K. Kasuga, T. Shimohata, A. Nishimura, A. Shiga, T. Mizuguchi, J. Tokunaga, T. Ohno, A. Miyashita, R. Kuwano, N. Matsumoto, O. Onodera, M. Nishizawa, T. Ikeuchi

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY80 ( 9 ) 1050 - 1052   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:B M J PUBLISHING GROUP  

    Background: The occurrence of duplications of the amyloid precursor protein gene (APP) has been described in European families with early-onset familial Alzheimer disease (EO-FAD) and cerebral amyloid angiopathy. However, the contribution of APP duplication to the development of AD in other ethnic populations remains undetermined.
    Methods: The occurrence of APP duplication in probands from 25 families with FAD and 11 sporadic EO-AD cases in the Japanese population was examined by quantitative PCR and microarray-based comparative genomic hybridisation analyses. APP expression level was determined by real-time quantitative reverse-transcription (RT) PCR analysis using mRNA extracted from the peripheral blood of the patients.
    Results: We identified APP locus duplications in two unrelated EO-FAD families. The duplicated genomic regions in two patients of these families differed from each other. No APP duplication was found in the late-onset FAD families or sporadic EO-AD patients. The patients with APP duplication developed insidious memory disturbance in their fifties without intracerebral haemorrhage and epilepsy. Quantitative RT-PCR analysis showed the increased APP mRNA expression levels in these patients compared with those in age- and sex-matched controls.
    Conclusions: Our results suggest that APP duplication should be considered in patients with EO-FAD in various ethnic groups, and that increased APP mRNA expression level owing to APP duplication contributes to AD development.

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  • Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation 査読

    Kensaku Kasuga, Tsukasa Ohno, Tomohiko Ishihara, Akinori Miyashita, Ryozo Kuwano, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    JOURNAL OF NEUROLOGY256 ( 8 ) 1351 - 1353   2009年8月

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    記述言語:英語   出版者・発行元:DR DIETRICH STEINKOPFF VERLAG  

    DOI: 10.1007/s00415-009-5096-4

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  • Novel GFAP Mutation in Patient with Adult-Onset Alexander Disease Presenting with Spastic Ataxia 査読

    Hiroyuki Kaneko, Masaki Hirose, Shinichi Katada, Toshiaki Takahashi, Satoshi Naruse, Miyuki Tsuchiya, Tomokatsu Yoshida, Masanori Nakagawa, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    MOVEMENT DISORDERS24 ( 9 ) 1393 - 1395   2009年7月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    DOI: 10.1002/mds.22556

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  • Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death 査読

    Mari Tada, Akiyoshi Kakita, Yasuko Toyoshima, Osamu Onodera, Tetsutaro Ozawa, Takashi Morita, Masatoyo Nishizawa, Hitoshi Takahashi

    BRAIN132 ( Pt 7 ) 1810 - 1819   2009年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 mu m sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 +/- 7.1 versus 75.2 +/- 7.6 cells, P &lt; 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 +/- 5.1 versus 72.8 +/- 13.6 cells, P &lt; 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 +/- 9.2 versus 60.8 +/- 17.0 cells, P &lt; 0.01), nucleus raphe obscurus (19.3 +/- 4.4 versus 75.3 +/- 8.6 cells, P &lt; 0.001), nucleus raphe pallidus (2.1 +/- 2.7 versus 9.0 +/- 3.4 cells, P &lt; 0.03), and arcuate nucleus (0.4 +/- 0.8 versus 2.3 +/- 1.5 cells, P &lt; 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 +/- 3.5 versus 21.8 +/- 6.5 cells, P &lt; 0.02) and nucleus raphe obscurus (15.0 +/- 2.0 versus 22.5 +/- 2.1 cells, P &lt; 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.

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  • Reliability of the Japanese version of the scale for the assessment and rating of ataxia (SARA) 査読

    Kazunori Sato, Ichiro Yabe, Hiroyuki Soma, Kenichi Yasui, Mizuki Ito, Takayoshi Shimohata, Osamu Onodera, Kenji Nakashima, Gen Sobue, Masatoyo Nishizawa, Hidenao Sasaki

    Brain and Nerve61 ( 5 ) 591 - 595   2009年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Background: The International Cooperative Ataxia Rating Scale (ICARS) is widely used as a scale for the assessment of the severity of cerebellar ataxia. However, this scale comprises several items
    thus, making the application of this scale is not sufficiently practical to perform daily assessment of ataxic patients. A new rating scale - Scale for the Assessment and Rating of Ataxia (SARA) - was shown to provide highly reliable assessments
    further, the scores on SARA correlated with the ICARS score and the Barthel index. After obtaining the permission, original SARA was translated into Japanese. Objective and Methods: To examine the reliability and internal consistency of the Japanese version of the SARA for the assessment of cerebellar ataxia in 66 patients with spinocerebellar degeneration. Results: Intraclass coefficients (ICC) were observed to be greater than 0.8 except in the case of the inter-rater "finger chase" and "fast alternating hand movement" tests. Conclusions: The Japanese version of SARA is highly reliable and very useful for the assessment of cerebellar ataxia on a daily basis.

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  • Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease 査読

    Kenju Hara, Atsushi Shiga, Toshio Fukutake, Hiroaki Nozaki, Akinori Miyashita, Akio Yokoseki, Hirotoshi Kawata, Akihide Koyama, Kunimasa Arima, Toshiaki Takahashi, Mari Ikeda, Hiroshi Shiota, Masato Tamura, Yutaka Shimoe, Mikio Hirayama, Takayo Arisato, Sohei Yanagawa, Akira Tanaka, Imaharu Nakano, Shu-ichi Ikeda, Yutaka Yoshida, Tadashi Yamamoto, Takeshi Ikeuchi, Ryozo Kuwano, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

    NEW ENGLAND JOURNAL OF MEDICINE360 ( 17 ) 1729 - 1739   2009年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MASSACHUSETTS MEDICAL SOC  

    BACKGROUND
    The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear.
    METHODS
    In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL.
    RESULTS
    We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta 1 in the tunica media.
    CONCLUSIONS
    CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

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  • Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice 査読

    Toshiya Sato, Masami Miura, Mitsunori Yamada, Takayuki Yoshida, Jonathan D. Wood, Ikuru Yazawa, Masao Masuda, Takeo Suzuki, Ryong-Moon Shin, Hau-Jie Yau, Fu-Chin Liu, Takayoshi Shimohata, Osamu Onodera, Christopher A. Ross, Motoya Katsuki, Hitoshi Takahashi, Masanobu Kano, Toshihiko Aosaki, Shoji Tsuji

    HUMAN MOLECULAR GENETICS18 ( 4 ) 723 - 736   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    We herein provide a thorough description of new transgenic mouse models for dentatorubral-pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and gamma-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions.

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  • A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions 査読

    Hiroaki Nozaki, Takayoshi Shimohata, Takashi Kanbayashi, Youhei Sagawa, Shin-ichi Katada, Masahisa Satoh, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

    SLEEP MEDICINE10 ( 2 ) 253 - 255   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Recent studies have demonstrated that hypothalamic lesions associated with brain tumor, head trauma, and encephalopathy can cause symptomatic hypersomnia with a reduced orexin (hypocretin) level in the cerebrospinal fluid (CSF). Aquaporin 4 (AQP4) a member of the AQP superfamily, is strongly expressed in the hypothalamus in which orexin (hypocretin)-containing neurons are primarily concentrated. We report the case of a patient with a serum anti-AQP4 antibody who presented with recurrent hypersomnia, symmetrical hypothalamic lesions with long spinal cord lesions oil MRI, and a reduced CSF orexin (hypocretin) level, all of which were improved simultaneously by steroid therapy. Further studies Should be performed to determine the roles of anti-AQP4 antibody positivity in patients with hypersomnia associated with orexin (hypocretin) deficiency and hypothalamic lesions. (c) 2009 Published by Elsevier B.V.

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  • Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. 査読

    Nishihira Yasushi, Tan Chun-Feng, Hoshi Yasuhiro, Iwanaga Keisuke, Yamada Megumi, Kawachi Izumi, Tsujihata Mitsuhiro, Hozumi Isao, Morita Takashi, Onodera Osamu, Nishizawa Masatoyo, Kakita Akiyoshi, Takahashi Hitoshi

    Acta Neuropathol117 ( 1 ) 45 - 53   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (&lt;5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule c

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  • Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology 査読

    Yasushi Nishihira, Chun-Feng Tan, Yasuhiro Hoshi, Keisuke Iwanaga, Megumi Yamada, Izumi Kawachi, Mitsuhiro Tsujihata, Isao Hozumi, Takashi Morita, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA117 ( 1 ) 45 - 53   2009年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (&lt; 5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

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  • Molecular mechanism for spinocerebellar ataxias 査読

    Osamu Onodera

    Clinical Neurology49 ( 11 ) 750 - 752   2009年

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    Recent advance of molecular biology reveals that quality control of intracellular environment takes an important role for maintaining the neuronal function. One is a quality control of protein and another is a quality control of nucleotide. Polyglutamine disease is a disease which caused by a failure of quality control of protein. Expanded polyglutamine repeats result in neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. About the quality control of nucleotide in neuron, DNA single-strand breaks (SSBs) were continually produced by endogenous reactive oxygen species or exogenous genotoxic agents. These damaged ends posses damaged 3′-ends including 3′-phosphate, 3′-phosphoglycolate, or 3′-α, β-unsaturated aldehyde ends, and should be restored to 3′-hydroxyl ends for subsequent repair processes. We have demonstrated by in vitro assay that aprataxin, the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ ataxia with oculomotor apraxia type 1 (EAOH/AOA1), specifically removes 3′-phosphoglycolate and 3′-phosphate ends at DNA 3′-ends, but not 3′-α, β-unsaturated aldehyde ends. The findings indicate that aprataxin removes blocking molecules from 3′-ends, and that the accumulation of unrepaired SSBs with damaged 3′-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.

    DOI: 10.5692/clinicalneurol.49.750

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  • Molecular mechanism for spinocerebellar ataxias 査読

    Osamu Onodera

    Clinical Neurology49 ( 1 ) 1 - 8   2009年

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    記述言語:日本語   出版者・発行元:Societas Neurologica Japonica  

    Recent advance of molecular biology reveals that quality control of intracellular environment takes an important role for maintaining the neuronal function. One is a quality control of protein and another is a quality control of nucleotide. Polyglutamine disease is a disease which caused by a failure of quality control of protein. Expanded polyglutamine repeats result in neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. We have applied fluorescence resonance energy transfer analysis to clarify the cytotoxicity of soluble polyglutamine oligomers. By using this method we revealed that polyglutamine monomers assemble into oligomer in a parallel β-sheet or a head-to-tail cylindrical β-sheet manner. We distinguished oligomers from monomers and inclusion bodies in a single living cell. Survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with inclusion bodies or monomers. These results indicate that a formation of oligomers is an essential mechanism underlying neurodegeneration in polyglutamine-mediated disorders. About the quality control of nucleotide in neuron, DNA single-strand breaks were continually produced by endogenous reactive oxygen species or exogenous genotoxic agents. These damaged ends posses damaged 3′-ends including 3′-phosphate, 3′-phosphoglycolate, or 3′-α, β-unsaturated aldehyde ends, and should be restored to 3′-hydroxyl ends for subsequent repair processes. We have demonstrated by in vitro assay that aprataxin, the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), specifically removes 3′-phosphoglycolate and 3′-phosphate ends at DNA 3′-ends, but not 3′-α, β-unsaturated aldehyde ends. The findings indicate that aprataxin removes blocking molecules from 3′-ends, and that the accumulation of unrepaired DNA single-strand breaks with damaged 3′-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons. Taken together, these results indicate that the quality control of protein and nucleotide is crucial to understand the neurodegenerative disorder.

    DOI: 10.5692/clinicalneurol.49.1

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  • Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy 査読

    Kiyoshi Egawa, Yukitoshi Takahashi, Yuko Kubota, Hideki Kubota, Yushi Inoue, Takeki Fujiwara, Osamu Onodera

    EPILEPSIA49 ( 12 ) 2041 - 2049   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    To clarify the electroclinical characteristics of epileptic seizures in patients with juvenile type dentatorubral-pallidoluysian atrophy (DRPLA).
    Seventeen patients with juvenile type DRPLA confirmed by genetic analysis were studied retrospectively. The clinical records of all 17 patients and the ictal video electroencephalography (EEG) recordings from 12 of the 17 patients were reviewed.
    Electroclinical studies in 12 patients identified 11 habitual seizures in 6 patients as partial seizures on ictal video EEG recordings. Clinical manifestations composed mainly of versions of the head and loss of consciousness. These partial seizures were persistently recorded throughout the clinical course. Brief generalized seizures (atypical absence and myoclonic seizure) were observed in 6 of 12 patients at the early stage. In contrast, generalized tonic-clonic seizures (GTCS) were recorded in four advanced stage patients who were almost bedridden. Semiological studies in 17 patients showed that the prevalence of partial seizures was significantly higher in patients with younger epilepsy onset (below 10 years of age; chi(2) test, p &lt; 0.05) and that the age of epilepsy onset was significantly lower in patients with partial seizures than in those without partial seizures (Mann-Whitney U test, p = 0.02). However, the number of CAG repeats and age at clinical onset were not significantly different between two groups.
    Partial seizure is one of the common epileptic features in juvenile type DRPLA, especially in patients with younger epilepsy onset. Seizure types may be affected in an age-dependent manner and change evolutionally during progression of the clinical stage.

    DOI: 10.1111/j.1528-1167.2008.01701.x

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  • Cardiac sympathetic denervation in Parkinson's disease linked to SNCA duplication 査読

    Satoshi Orimo, Toshiki Uchihara, Ayako Nakamura, Fumiaki Mori, Takeshi Ikeuchi, Osamu Onodera, Masatoyo Nishizawa, Atsushi Ishikawa, Akiyoshi Kakita, Koichi Wakabayashi, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA116 ( 5 ) 575 - 577   2008年11月

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    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s00401-008-0428-5

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  • Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis 査読

    Yuji Takahashi, Naomi Seki, Hiroyuki Ishiura, Jun Mitsui, Takashi Matsukawa, Atsushi Kishino, Osamu Onodera, Masashi Aoki, Nobuyuki Shimozawa, Shigeo Murayama, Yasuto Itoyama, Yasuyuki Suzuki, Gen Sobue, Masatoyo Nishizawa, Jun Goto, Shoji Tsuji

    ARCHIVES OF NEUROLOGY65 ( 10 ) 1326 - 1332   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: Comprehensive resequencing of the causative and disease-related genes of neurodegenerative diseases is expected to enable (1) comprehensive mutational analysis of familial cases, (2) identification of sporadic cases with de novo or low-penetrant mutations, (3) identification of rare variants conferring disease susceptibility, and ultimately (4) better understanding of the molecular basis of these diseases.
    Objective: To develop a microarray-based high-throughput resequencing system for the causative and disease-related genes of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
    Design: Validation of the system was conducted in terms of the signal-to-noise ratio, accuracy, and throughput. Comprehensive gene analysis was applied for patients with ALS.
    Subjects: Ten patients with familial ALS, 35 patientswith sporadic ALS, and 238 controls.
    Results: The system detected point mutations with 100% accuracy and completed the resequencing of 270 kilobase pairs in 3 working days with greater than 99.9% accuracy of base calls, or the determination of base(s) at each position. Analysis of patients with familial ALS revealed 2 SOD1 mutations. Analysis of the 35 patients with sporadic ALS revealed a previously known SOD1 mutation, S134N, a novel putative pathogenic DCTN1 mutation, R997W, and 9 novel variants including 4 nonsynonymous heterozygous variants consisting of 2 in ALS2, 1 in ANG, and 1 in VEGF that were not found in the controls.
    Conclusion: The DNA microarray-based resequencing system is a powerful tool for high-throughput comprehensive analysis of causative and disease-related genes. It can be used to detect mutations in familial and sporadic cases and to identify numerous novel variants potentially associated with genetic risks.

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  • Marinesco-Sjögren syndrome with atrophy of the brain stem tegmentum and dysplastic cytoarchitecture in the cerebral cortex. 査読

    Sakai K, Tada M, Yonemochi Y, Nakajima T, Onodera O, Takahashi H, Kakita A

    Neuropathology : official journal of the Japanese Society of Neuropathology28 ( 5 ) 541 - 546   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/j.1440-1789.2008.00884.x

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  • Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population 査読

    M. Iijima, H. Koike, N. Hattori, A. Tamakoshi, M. Katsuno, F. Tanaka, M. Yamamoto, K. Arimura, G. Sobue, S. Yagihashi, T. Yamamura, S. Ikeda, M. Nakagawa, S. Kusunoki, K. Inoue, K. Hayasaka, K. Matsumura, Y. Ando, M. Baba, M. Nakazato, H. Yasuda, R. Kaji, O. Onodera, J. Kira, S. Kuwabara, K. Arimura, G. Sobue

    Journal of Neurology, Neurosurgery and Psychiatry79 ( 9 ) 1040 - 1043   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective and methods: To characterise the epidemiological features of chronic inflammatory demyelinating polyneuropathy (CIDP) in the Japanese population, this study performed a nationwide assessment of the prevalence and incidence rates in Japan. Results: The prevalence rate per 100 000 was 1.61 in the total population
    2.01 in males and 1.23 in females. The age dependent prevalence rates were 0.23 in juveniles (&lt
    15 years old), 1.50 in young adults (15-55 years) and 2.31 in elderly adults (&gt
    55 years). The sex and age dependent prevalence rates were 0.22 in males and 0.24 in females in juveniles, 1.81 in males and 1.19 in females in young adults, and 3.12 in males and 1.64 in females in elderly adults. The annual incidence rate per 100 000 was 0.48 in the total population, 0.58 in males and 0.38 in females. The age dependent incidence rate was 0.06 in juveniles, 0.40 in young adults and 0.73 in elderly adults. The sex and age dependent incidence rate was 0.05 in males and 0.08 in females in juveniles, 0.50 in males and 0.30 in females in young adults, and 0.93 in males and 0.58 in females in elderly adults. Both the prevalence and incidence rates were very similar throughout the eight geographical areas studied, from the northern to the southern parts of Japan. Conclusions: The prevalence and incidence rates were similar to those reported in the Caucasian population. The pathogenic background is suggested to be common throughout the different races and geographic areas, while gender and age effects should be taken into account in the pathogenesis of CIDP.

    DOI: 10.1136/jnnp.2007.128132

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  • Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

    K. Hara, A. Shiga, H. Nozaki, J. Mitsui, Y. Takahashi, H. Ishiguro, H. Yomono, H. Kurisaki, J. Goto, T. Ikeuchi, S. Tsuji, M. Nishizawa, O. Onodera

    NEUROLOGY71 ( 8 ) 547 - 551   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background: Spinocerebellar ataxia type 15 (SCA15) is a progressive neurodegenerative disorder characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. The locus for SCA15 was first mapped to 3p24.2-3pter in an Australian family. We have subsequently mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk to the SCA15 locus. Recently, partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase modifying factor 1 (SUMF1) genes have been identified in Australian and British families with SCA15.
    Methods: We conducted fine haplotype analysis on the region including ITPR1. To identify the deletion, we conducted gene dosage analysis and array-based comparative genomic hybridization (aCGH) analysis. Gene expression analysis was performed using quantitative real-time reverse transcription PCR. Mutational analyses of ITPR1 and SUMF1 were also performed.
    Results: We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in family A. The expression levels of ITPR1 and SUMF1 mRNAs of the patient were half those of the normal control. Furthermore, in family B, we have identified a C-to-T substitution at position 8581 of ITPR1, resulting in the amino acid substitution of leucine for proline at codon 1059, which is highly conserved among species.
    Conclusions: Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

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  • Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions 査読

    Yasushi Nishihira, Chun-Feng Tan, Osamu Onodera, Yasuko Toyoshima, Mitsunori Yamada, Takashi Morita, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA116 ( 2 ) 169 - 182   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.

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  • Sporadic ataxias in Japan - a population-based epidemiological study 査読

    Shoji Tsuji, Osamu Onodera, Jun Goto, Masatoyo Nishizawa

    CEREBELLUM7 ( 2 ) 189 - 197   2008年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Sporadic spinocerebellar ataxias (SCAs) comprise heterogeneous diseases with poorly understood epidemiologies and etiologies. A population-based epidemiological analysis of sporadic ataxias in the Japanese population was described. The prevalence rate of SCAs in the Japanese population is estimated to be 18.5/100,000. Sporadic SCAs account for 67.2% of total SCAs including hereditary SCAs, with olivopontocerebellar atrophy (OPCA) being the most common form sporadic ataxia (64.7%). The natural history analysis conducted on the basis of International Cooperative Ataxia Rating Scale (ICARS) showed that only 33% of patients with OPCA were able to walk at least with one stick 4-5 years after the onset of OPCA, which is much less than that of patients with cortical cerebellar atrophy (CCA). Similarly, 43% of patients with OPCA were able to stand alone 4-5 years after the onset, while 76% of patients with CCA were able to stand alone at the same disease duration. A population-based epidemiological analysis should provide essential information on the natural history of SCAs.

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis 査読

    Akio Yokoseki, Atsushi Shiga, Chun-Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizava, Hitoshi Takahashi, Osamu Onodera

    ANNALS OF NEUROLOGY63 ( 4 ) 538 - 542   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Accumulating evidence has shown that 43kDa TAR-DNA-binding protein (TDP-43) is the disease protein in ALS and frontotemporal lobar degeneration. We previously reported a familial ALS with Bumina bodies and TDP-43-positive skein-like inclusions in the lower motor neurons; these findings are indistinguishable from those of sporadic ALS. In three affected individuals in two generations of one family, we found a single base-pair change from A to G at position 1028 in TDP-43, which resulted in a Gln-to-Arg substitution at position 343. Our findings provide a new insight into the molecular pathogenesis of ALS.

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  • Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia 査読

    Takeshi Ikeuchi, Akiyoshi Kakita, Atsushi Shiga, Kensaku Kasuga, Hiryoyuki Kaneko, Chun-Feng Tan, Jiro Idezuka, Koichi Wakabayashi, Osamu Onodera, Takeshi Iwatsubo, Masatoyo Nishizawa, Hitoshi Takahashi, Atsushi Ishikawa

    ARCHIVES OF NEUROLOGY65 ( 4 ) 514 - 519   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: Multiplication of the alpha-synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies.
    Objective: To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.
    Design: Four-generation family study.
    Setting: Academic research.
    Patients: We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.
    Main Outcome Measures: We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.
    Results: Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated alpha-synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.
    Conclusions: Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients.

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  • Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic 査読

    Toshiaki Takahashi, Shinya Kikuchi, Shinichi Katada, Yoshitaka Nagai, Masatoyo Nishizawa, Osamu Onodera

    HUMAN MOLECULAR GENETICS17 ( 3 ) 345 - 356   2008年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Expanded polyglutamine (polyQ) repeats cause neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. Although soluble polyQ oligomers have been proposed as a cytotoxic structure, the cytotoxicity of soluble polyQ oligomers, not inclusion bodies (IBs), has not been proven in living cells. To clarify the cytotoxicity of soluble polyQ oligomers, we carried our fluorescence resonance energy transfer (FRET) confocal microscopy and distinguished oligomers from monomers and IBs in a single living cell. FRET signals were detected when donor and acceptor fluorescent proteins were attached to the same side, not the opposite side, of polyQ repeats, which agrees with a parallel beta-sheet or a head-to-tail cylindrical beta-sheet model. These FRET signals disappeared in semi-intact cells, indicating that these polyQ oligomers are soluble. PolyQ monomers assembled into soluble oligomers in a length-dependent manner, which was followed by the formation of IBs. Notably, survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with IBs or monomers. These results indicate that a length-dependent formation of oligomers is an essential mechanism underlying neurodegeneration in polyQ-mediated disorders.

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  • The clinical-genealogic and molecular-genetic characteristics of oculopharyngeal muscular dystrophy in the Republic of Sakha (Yakutia) 査読

    N. R. Maksimova, I. A. Nikolaeva, M. N. Korotov, T. Ikeuchi, O. Onodera, M. Nishizawa, S. K. Stepanova, Kh. A. Kurtanov, A. L. Sukhomyasova, A. N. Nogovitcina, E. E. Gurinova, V. A. Stepanov, V. P. Puzyrev

    ZHURNAL NEVROLOGII I PSIKHIATRII IMENI S S KORSAKOVA108 ( 6 ) 52 - 60   2008年

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    記述言語:ロシア語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IZDATELSTVO MEDITSINA  

    The clinical-genealogic and molecular-genetic investigation of oculopharyngeal muscular dystrophy (OPMD) in the Republic of Sakha (Yakutia) was performed. it was investigated 33 unrelated yakut families with 38 patients and 2 russian families with 2 patients and 59 their healthy relatives as well. The high clinical polymorphism of disease was found in patients with OPMD. The mutation in exon 1 of the PABPN1 gene resulting in the expansion of GCG-repeats up to 10 is revealed. Using direct sequencing of the PABPN1 gene in 17 families (16 yakut, 1 russian), we identified a type of this mutation as an insertion of 4 GCG-repeats. Frequency of OPMD in the yakut population is 1:11 680 that is 10-20 times higher comparing to european populations. This is a first report on the patients with OPMD from the Republic of Sakha with diagnosis confirmed by molecular-genetic analysis.

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  • Mutational analysis in early-onset familial dementia in the Japanese population 査読

    Takeshi Ikeuchi, Hiroyuki Kaneko, Akinori Miyashita, Hiroaki Nozaki, Kensaku Kasuga, Tamao Tsukie, Miyuki Tsuchiya, Toru Imamura, Hideki Ishizu, Kenju Aoki, Atsushi Ishikawa, Osamu Onodera, Ryozo Kuwano, Masatoyo Nishizawa

    DEMENTIA AND GERIATRIC COGNITIVE DISORDERS26 ( 1 ) 43 - 49   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background: Three major causative genes have been implicated as the cause of early-onset familial Alzheimer's disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD. Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer's disease. Results: In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems. Conclusion: These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied. Copyright (c) 2008 S. Karger AG, Basel.

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  • Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families 査読

    Hiroaki Nozaki, Kenju Hara, Atsushi Shiga, Jun Mitsui, Yuuji Takahashi, Hideaki Ishiguro, Harumi Shimono, Hiroshi Kurisaki, Jun Goto, Takeshi Ikeuchi, Shouji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    NEUROSCIENCE RESEARCH61   S206 - S206   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis 査読

    Akio Yokoseki, Atsushi Shiga, Chun Feng Tan, Asako Tagawa, Hiroyuki Kaneko, Akihide Koyama, Hiroto Eguchi, Akira Tsujino, Takeshi Ikeuchi, Akiyoshi Kakita, Koichi Okamoto, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    NEUROSCIENCE RESEARCH61   S267 - S267   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Contribution of APP duplication as a cause in a cohort of Japanese Alzheimer disease patients 査読

    Kensaku Kasuga, Atsushi Shiga, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Takeshi Ikeuchi

    NEUROSCIENCE RESEARCH61   S264 - S264   2008年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia 査読

    N. Maksimova, K. Hara, A. Miyashia, I. Nikolaeva, A. Shiga, A. Nogovicina, A. Sukhomyasova, V. Argunov, A. Shvedova, T. Ikeuchi, M. Nishizawa, R. Kuwano, O. Onodera

    JOURNAL OF MEDICAL GENETICS44 ( 12 ) 772 - 778   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Background: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified.
    Methods: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut.
    Results: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 ( Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation.
    Conclusion: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

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  • Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 Delta T440 mutant associated with familial Lewy body disease and variant Alzheimer's disease 査読

    Hiroyuki Kaneko, Akiyoshi Kakita, Kensaku Kasuga, Hiroaki Nozaki, Atsushi Ishikawa, Akinori Miyashita, Ryozo Kuwano, Genta Ito, Takeshi Iwatsubo, Hitoshi Takahashi, Masatoyo Nishizawa, Osamu Onodera, Sangram S. Sisodia, Takeshi Ikeuchi

    JOURNAL OF NEUROSCIENCE27 ( 48 ) 13092 - 13097   2007年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Mutations in the PSEN1 gene encoding presenilin 1 ( PS1) are linked to a vast majority of pedigrees with early- onset, autosomal dominant forms of familial Alzheimer's disease ( FAD). Lewy body ( LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (Delta T440) in a familial case diagnosed as having the neocortical type of dementia with LBs ( DLB) and variant AD. In this report, we investigated the possible involvement of PS1 Delta T440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild- type ( WT) PS1 or the FAD- linked PS1 H163R, E280A, Delta E9, and PS1 Delta T440 mutants and now demonstrate that the expression of the PS1 Delta T440 mutant led to a marked elevation in the ratio of beta-amyloid (A beta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non- neuronal cells expressing the PS1 Delta T440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 Delta T440 mutation. These observations raise the intriguing suggestion that the mechanism( s) by which the PS1 Delta T440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of A beta(42/40) peptides, respectively, in the brain.

    DOI: 10.1523/JNEUROSCI.4244-07.2007

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  • Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読 国際誌

    Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

    Brain : a journal of neurology130 ( Pt 9 ) 2302 - 9   2007年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

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  • Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3 q23.3. 査読 国際誌

    Takayoshi Shimohata, Kenju Hara, Kazuhiro Sanpei, Jin-ichi Nunomura, Tetsuya Maeda, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

    Brain : a journal of neurology130 ( Pt 9 ) 2302 - 9   2007年9月

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    記述言語:英語  

    Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

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  • Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase 査読

    K. Kasuga, H. Kaneko, M. Nishizawa, O. Onodera, T. Ikeuchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS360 ( 1 ) 90 - 96   2007年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The proteolytic cleavage of a precursor protein into alpha- and beta-subunits by furin is required to form functional insulin receptor (IR). In this study, we examined if IR undergoes the additional presenilin (PS)/gamma- secretase-dependent processing. In cells treated with gamma-secretase inhibitors or expressing the dominant-negative PS1 variant led to the accumulation of an endogenous IR C-terminal fragment. In the presence of proteasome inhibitors, we detected a PS/gamma-secretase cleavage product of the IR, termed the IR intracellular domain (ICD). Cellular fractionation and confocal microscopy analyses showed that the IR-ICD is predominantly detected in the nucleus. These data indicate that IR is a tyrosine kinase receptor, which undergoes PS/gamma-secretase-dependent processing. We also show that the auto-phosphorylation levels of the IR P-subunit upon insulin stimulation were decreased by the inactivation of PS/gamma-secretase, raising the possibility that the PS/gamma-secretase proteolysis of IR may play a modulatory role in insulin signaling. (c) 2007 Elsevier Inc. All rights reserved.

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  • Sacsin-related ataxia with neither retinal hypermyelination nor spasticity 査読

    Kenju Hara, Junsuke Shimbo, Hiroaki Nozaki, Koki Kiku-Awa, Osamu Onodera, Masatoyo Nishizawa

    MOVEMENT DISORDERS22 ( 9 ) 1362 - 1363   2007年7月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

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  • Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3 '-phosphate and 3 '-phosphoglycolate ends 査読

    Tetsuya Takahashi, Masayoshi Tada, Shuichi Igarashi, Akihide Koyama, Hidetoshi Date, Akio Yokoseki, Atsushi Shiga, Yutaka Yoshida, Shoji Tsuji, Masatoyo Nishizawa, Osamu Onodera

    NUCLEIC ACIDS RESEARCH35 ( 11 ) 3797 - 3809   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.

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  • Daytime hypoxemia, sleep-disordered breathing, and laryngopharyngeal findings in multiple system atrophy 査読

    Takayoshi Shimohata, Hideo Shinoda, Hideaki Nakayama, Tetsutaro Ozawa, Kenshi Terajima, Hirohisa Yoshizawa, Yoko Matsuzawa, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Sugata Takahashi, Fumitake Gejyo, Masatoyo Nishizawa

    ARCHIVES OF NEUROLOGY64 ( 6 ) 856 - 861   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: The mechanism underlying nocturnal sudden death in patients with MSA remains unclear. It may be explained by upper airway obstruction, such as vocal cord abductor paralysis; an impairment of the respiratory center, such as Cheyne- Stokes respiration; or an impaired hypoxemic ventilatory response.
    Objective: To investigate the mechanism of sleep-disordered breathing in multiple system atrophy ( MSA).
    Design: We recruited 21 patients with probable MSA who were admitted sequentially to our hospital, and performed daytime blood gas analysis, pulmonary function tests, polysomnography, and fiberoptic laryngoscopy during wakefulness and with the patient under anesthesia.
    Results: A decrease in arterial oxygen pressure and an increase in alveolar- arterial oxygen gradient significantly correlated with disease duration ( P=. 045 and.046, respectively). Polysomnography demonstrated CheyneStokes respiration in 3 ( 15%) of 20 patients. Fiberoptic laryngoscopy during wakefulness showed that 3 ( 14%) of the 21 patients exhibited vocal cord abductor paralysis, and laryngoscopy under anesthesia showed that 9 ( 45%) of 20 patients exhibited vocal cord abductor paralysis. Laryngoscopy under anesthesia also revealed that 11 ( 55%) of 20 patients showed upper airway obstruction in places other than the vocal cords, including obstruction at the base of the tongue or soft palate. In addition, it demonstrated novel laryngopharyngeal findings, such as floppy epiglottis and airway obstruction at the arytenoid.
    Conclusions: We observed daytime hypoxemia with an increased alveolar- arterial oxygen gradient, CheyneStokes respiration, and novel abnormal laryngopharyngeal movements in patients with MSA. We also found that laryngoscopy under anesthesia might be useful for evaluating upper airway obstruction. The significance of these findings to the mechanism of sudden death in those with MSA needs to be examined.

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  • TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation 査読

    Chun-Feng Tan, Hiroto Eguchi, Asako Tagawa, Osamu Onodera, Takuya Iwasaki, Akira Tsujino, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA113 ( 5 ) 535 - 542   2007年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.

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  • New mutation in the non-gigantic exon of SACS in Japanese siblings 査読

    Yuhei Takado, Kenju Hara, Takayoshi Shimohata, Susumu Tokiguchi, Osamu Onodera, Masatoyo Nishizawa

    MOVEMENT DISORDERS22 ( 5 ) 748 - 749   2007年4月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    DOI: 10.1002/mds.21365

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  • Multiplex families with multiple system atrophy 査読

    Kenju Hara, Yoshio Momose, Susumu Tokiguchi, Mitsuteru Shimohata, Kenshi Terajima, Osamu Onodera, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Motoyuki Hirasawa, Yoshikuni Mizuno, Katsuhisa Ogata, Jun Goto, Ichiro Kanazawa, Masatoyo Nishizawa, Shoji Tsuji

    ARCHIVES OF NEUROLOGY64 ( 4 ) 545 - 551   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance.
    Objective: To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects.
    Design: Clinical and genetic study. Setting: Four departments of neurology in Japan.
    Patients: Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions.
    Main Outcome Measures: Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the alpha-synuclein gene was performed.
    Results: Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-synuclein gene were found.
    Conclusions: Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.

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  • Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population 査読

    Hiroaki Nozaki, Takeshi Ikeuchi, Akio Kawakami, Akio Kimura, Reiji Koide, Miyuki Tsuchiya, Yuusaku Nakmura, Tatsuro Mutoh, Hiroko Yamamoto, Naoki Nakao, Ko Sahashi, Masatoyo Nishizawa, Osamu Onodera

    MOVEMENT DISORDERS22 ( 6 ) 857 - 862   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranstated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/ SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60. (c) 2007 Movement Disorder Society.

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  • Botulinum toxin A injections improve apraxia of eyelid opening without overt blepharospasm associated with neurodegenerative diseases 査読

    Masato Kanazawa, Takayoshi Shimohata, Masahisa Sato, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

    MOVEMENT DISORDERS22 ( 4 ) 597 - 598   2007年3月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    DOI: 10.1002/mds.21367

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  • New locus for benign hereditary chorea with adult-onset maps to chromosome 8q22.2-q23.3 査読

    Kenju Hara, Takayoshi Shimohata, Sanpei Kazuhiro, Jin-ichi Nunomura, Izumi Kawachi, Masato Kanazawa, Kensaku Kasuga, Akinori Miyashita, Ryozo Kuwano, Koichi Hirota, Shoji Tsuji, Osamu Onodera, Masatoyo Nishizawa, Yoshiaki Honma

    NEUROLOGY68 ( 12 ) A326 - A327   2007年3月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons 査読

    Asako Tagawa, Chun-Feng Tan, Koki Kikugawa, Masayuki Fukase, Ryoichi Nakano, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA113 ( 2 ) 205 - 211   2007年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke&apos;s column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.

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  • Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy 査読

    Mari Tada, Osamu Onodera, Masayoshi Tada, Tetsutaro Ozawa, Yue-Shan Piao, Akiyoshi Kakita, Hitoshi Takahashi, Masatoyo Nishizawa

    ARCHIVES OF NEUROLOGY64 ( 2 ) 256 - 260   2007年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: Multiple system atrophy (MSA) is diverse in clinical phenotype, disease progression, and prognosis. Sudden death is a leading cause of death in patients with MSA.
    Objective: To determine what clinical factors affect the progression and survival prognosis of those with MSA.
    Design: A retrospective review of the medical records of 49 consecutive Japanese patients with pathologically confirmed MSA ( 29 men and 20 women; mean +/- SD age at onset, 59.8 +/- 6.5 years). Cox proportional hazards models were used to compare the risks of being in a wheel-chair-bound state, being in a bedridden state, and having a shorter survival.
    Results: Thirty-one patients were diagnosed as having cerebellar type MSA, and 18 were diagnosed as having parkinsonian type MSA. Twenty-nine patients with cerebellar type MSA and 17 patients with parkinsonian type MSA had autonomic dysfunction. The median times from disease onset to being in a wheel-chair-bound state, being in a bedridden state, death, and the development of autonomic dysfunction were 3.5, 5.0, 7.0, and 2.5 years, respectively. Patients with an early development of autonomic dysfunction (within 2.5 years from the onset of MSA) had significantly higher risks of being in a wheel-chair-bound state (multivariate-adjusted hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.04-9.15), being in a bedridden state (HR, 3.87; 95% CI, 1.77-8.48), having a shorter survival (HR, 3.40; 95% CI, 1.61-7.15), and sudden death (HR, 7.22; 95% CI, 1.49-35.07).
    Conclusion: The early development of autonomic dysfunction is an independent predictive factor for rapid disease progression and shorter survival in patients with MSA.

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  • Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter 査読

    Masaru Matsui, Kotaro Mizutani, Hiroaki Ohtake, Yukio Miki, Koichi Ishizu, Hidenao Fukuyama, Takayoshi Shimohata, Osamu Onodera, Masatoyo Nishizawa, Yoshihiro Takayama, Hiroshi Shibasaki

    EUROPEAN NEUROLOGY57 ( 1 ) 57 - 58   2007年

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    記述言語:英語   出版者・発行元:KARGER  

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  • Spinocerebellar ataxia with ocular motor apraxia and DNA repair 査読

    Osamu Onodera

    NEUROPATHOLOGY26 ( 4 ) 361 - 367   2006年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    At least four disorders, ataxia telangiectasia (AT), an ataxia-telangiectasia-like disorder, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2, are accompanied by ocular motor apraxia (OMA), which is an impairment of saccadic eye movement initiation. The characteristic pathological findings of EAOH/AOA1 and AT are a severe loss of Purkinje cells, severe myelin pallor of the posterior columns, and moderate neuronal loss in the dorsal root ganglia and anterior horn. Purkinje cells stimulate the fastigial nucleus and suppress omnipause neurons to initiate saccadic eye movement. The selective loss of Purkinje cells might cause OMA and disturb the cancellation of the vestibulo-ocular reflex. These disorders have the following common clinical features: ataxia, involuntary movements, and peripheral neuronopathy. In addition, the causative genes for these disorders are associated with the DNA/RNA quality control system. The impairment of DNA/RNA integrity results in selective neuronal loss in these recessive-inherited ataxias.

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  • Long-terms therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis 査読

    Masayoshi Tada, Takayoshi Shimohata, Mari Tada, Mutsuo Oyake, Shuichi Igarashi, Osamu Onodera, Satoshi Naruse, Keiko Tanaka, Shoji Tsuji, Masatoyo Nishizawa

    JOURNAL OF THE NEUROLOGICAL SCIENCES247 ( 1 ) 17 - 20   2006年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Objective: To elucidate the long-term therapeutic efficacy and safety of low-dose FK506 (tacrolimus) in patients with myasthenia gravis (MG).
    Patients and methods: We treated nine patients with MG (all women: age range: 35-83years (mean: 51.1 years); MGFA classification: 4 type IIa, 4 type IIb, and 1 type IVb patients) with FK506 for more than 24months (observation period: 24-46months). All the patients had undergone extended thymectomy before FK506 treatment; two patients (22.2%) had noninvasive thymoma and six (66.7%) had thymic hyperplasia. We evaluated total Quantitative MG (Q-MG) score, anti-acetylcholine receptor (AM) antibody titer in the blood, interleukin 2 (IL-2) production in peripheral blood mononuclear cells (PBMCs), administration dosage of prednisolone (PSL), and adverse effects of FK506.
    Results: A reduction in steroid dosage of 50 50% without worsening of the symptoms was observed 1 year after FK506 administration in three out of six steroid-dependent MG patients (50.0%). The total Q-MG scores (range: 0-39 points) at 6months and l year after FK506 administration improved by 3 points or more in six (66.7%) and seven (77.8 %) out of nine patients, respectively. The efficacy of FK506 was maintained for more than 2years. Although adverse effects were observed in three patients (33.3 %), these were not serious.
    Conclusions: Our study indicates that low-dose FK506 treatment may be efficacious not only in controlling intractable myasthenic symptoms, but also in reducing steroid dosage, and that FK506 is safe as an adjunctive drug to PSL for MG treatment for a maximum of 3 years. (c) 2006 Elsevier B.V. All rights reserved.

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  • New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2 査読

    M Takagi, T Ozawa, K Hara, S Naruse, T Ishihara, J Shimbo, S Igarashi, K Tanaka, O Onodera, M Nishizawa

    NEUROLOGY66 ( 8 ) 1251 - 1252   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Hereditary sensory and autonomic neuropathies (HSANs) are heterogenous disorders characterized by a loss of pain sensation and autonomic abnormalities caused by peripheral nerve degeneration. (1) HSANs are clinically classified into five entities based on the inheritance pattern and clinical presentations. Mutations in at least six genes, SPTLC1, RAB7, HSN2, IKBKAP, TRKA, and NGFB, are known to be causative for the clinical varieties of HSANs. (1)
    HSAN2 is clinically characterized by autosomal recessive inheritance, the onset of symptoms in infancy or early childhood, the occurrence of paronychia, whitlows, ulcers of distal extremities, unrecognized fractures of the foot and hand, anhidrosis, sensory loss that affects all modalities of sensations in the lower and upper limbs, the absence or diminution of tendon reflexes, the absence of sensory nerve action potentials (SNAPs), and the virtual absence of myelinated fibers with a decreased number of unmyelinated fibers in sural nerves. (1)
    To date, seven truncated mutations of the HSN2 gene have been identified among HSAN2 families from Quebec, Newfoundland, and Nova Scotia in Canada, and Lebanon, Italy, and Austria. (2-5) Here, we describe a new truncated mutation in the HSN2 gene of a Japanese patient with HSAN2.

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  • Oral cyclophosphamide therapy for multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis 査読

    Masayoshi Tada, Osamu Onodera, Kenju Hara, Keiko Tanaka, Hitoshi Takahashi, Shoji Tsuji, Masatoyo Nishizawa

    Clinical Neurology46 ( 2 ) 128 - 133   2006年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 54-year-old man was admitted to our hospital because of a headache, dry cough, low grade fever and hearing loss sustained for 6 months. Physical and neurological examinations revealed bilateral conjunctival hyperemia, fine crackles in the lower lungs, cutaneous scars, horizontal gaze evoked nystagmus, bilateral moderate sensorineural deafness and mild hyperreflexia. Hypertrophic intracranial pachymeningitis (HIP) accompanied by episcleritis, pulmonary fibrosis, subcutaneous fibrosis of the trunk and upper limbs, bilateral chronic otitis media and sinusitis of the paranasal cavities were observed. Histopathological investigation of biopsied tissues from the dura matter, lung, skin and nasal mucosa showed marked fibrosis with lymphocyte and plasma cell infiltrations. The diagnosis of multifocal fibrosclerosis (MF) was made
    this is a rare syndrome of unknown etiology characterized by fibrosis involving multiple organ systems. Although steroid pulse therapy and cyclophosphamide (CP) pulse therapy was not effective in his illnesses, the combination therapy of corticosteroid and oral CP was dramatically effective. We concluded that HIP can be a manifestation of MF, and additional oral CP should be considered as a treatment for steroid-resistant MF with HIP.

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  • Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast 査読

    J Shimbo, O Onodera, K Tanaka, S Tsuji

    CLINICAL RHEUMATOLOGY24 ( 6 ) 661 - 662   2005年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    The authors studied eight cases of Churg-Strauss syndrome (CSS) associated with the use of pranlukast, a common cysteinyl leukotriene receptor antagonist (LTRA) in Japan. The patients who received pranlukast showed significantly increased peripheral blood eosinophil count, neurological disability scores, and poor responses to corticosteroid in comparison with those patients not receiving pranlukast. We suggest that preceding administration of pranlukast aggravates clinical presentations of CSS.

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  • DNA repair and neurodegeneration 査読

    Osamu Onodera

    Clinical Neurology45 ( 11 ) 979 - 981   2005年11月

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    記述言語:日本語   掲載種別:研究論文(国際会議プロシーディングス)  

    Early onset ataxia with hypoalbuminemia (AOA1/EAOH) patients begin with ocular motor apraxia and cerebellar ataxia in childhood, and then develop axonal peripheral neuropathy and hypoalbuminemia. We and others identified 'aprataxin (APTX) ' as the causative gene for AOA1/EAOH. APTX binds to XRCC1, which is the scaffold protein for BER machinery, and has a HIT-motif, which is supposed to have hydrolase activity on nucleotide. These properties suggest that APTX acts on DNA during single strand DNA break. The 3′-termini of single strand DNA break must be hydroxylated to allow DNA polymerase or ligase to repair
    however, ordinary the 3′-termini is modified by phosphate or others. These unsuitable ends have to be removed to repair. To investigate whether the APTX works on DNA and remove the unsuitable 3′-end, we incubated recombinant human APTX with variable oligonucleotide. We show that APTX has bidirectional exonuclease activity and 3′-phosphatase activity. These results indicate that APTX might modify the phosphorylated 3′-end in a single strand DNA break. To date several diseases have been identified as caused by an impairment of quality control system of DNA/ RNA. The impairment of quality control system of DNA/RNA is a new pathway for neuronal degeneration.

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  • Selective silencing of a mutant transthyretin allele by small interfering RNAs 査読

    T Kurosawa, S Igarashi, M Nishizawa, O Onodera

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS337 ( 3 ) 1012 - 1018   2005年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis caused by dominantly acting missense mutations in the gene encoding transthyretin (TTR). The most common mutant TTR is of the Va130Met type, which results from a point mutation. Because the major constituent of amyloid fibrils is mutant TTR, agents that selectively suppress mutant TTR expression could be powerful therapeutic tools. This study has been performed to evaluate the use of small interfering RNAs (siRNAs) for the selective silencing of mutant Va130Met TTR in cell culture systems. We have identified an siRNA that specifically inhibits mutant, but not wild-type, TTR expression even in cells expressing both alleles. Thus, this siRNA-based approach may have potential for the gene therapy of FAR (c) 2005 Elsevier Inc. All rights reserved.

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  • Natural history of X-linked adrenoleukodystrophy in Japan 査読

    Y Suzuki, Y Takemoto, N Shimozawa, T Imanaka, S Kato, H Furuya, M Kaga, K Kato, N Hashimoto, O Onodera, S Tsuji

    BRAIN & DEVELOPMENT27 ( 5 ) 353 - 357   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    The natural history of X-linked adrenoleukodystrophy (ALD) was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adolescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed. Initial symptoms of the childhood cerebral form were intellectual (n=16) and visual (n = 11) disturbances, whereas those of AMN were gait (n = 37) and sensory (n = 3) disturbances; the adult cerebral form, psychic (n= 19) and gait (n = 11)disturbances; the adolescent form, visual n = 5) and gait (n = 4) disturbances; and the OPC form, gait (n = 9) disturbance. Patients with onset under the age of 8 years progressed more rapidly than those over 8 years old. Visual, hearing, gait and swallowing disturbances progressed more slowly in the older group. About half of AMN patients showed cerebral involvement about 10 years after onset. Patients with the OPC form also showed a similar progression. A Kaplan-Meier plot clarified the characteristic pattern of progression of neurological symptoms in each phenotype. These finding will improve the understanding of the natural history of X-linked ALD and will provide a basis for the evaluation of specific treatment for X-linked ALD. (c) 2004 Elsevier B.V. All rights reserved.

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  • Age associated axonal features in HNPP with 17p11.2 deletion in Japan 査読

    H Koike, M Hirayama, M Yamamoto, H Ito, N Hattori, F Umehara, K Arimura, S Ikeda, Y Ando, M Nakazato, R Kaji, K Hayasaka, M Nakagawa, S Sakoda, K Matsumura, O Onodera, M Baba, H Yasuda, T Saito, J Kira, K Nakashima, N Oka, G Sobue

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY76 ( 8 ) 1109 - 1114   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:B M J PUBLISHING GROUP  

    Objective: To clarify age related changes in the clinicopathological features of hereditary neuropathy with liability to pressure palsy ( HNPP) in Japanese patients with deletion of 17p11.2, particularly concerning axonal abnormalities.
    Methods: Forty eight proband patients from 48 HNPP families were assessed as to clinical, electrophysiological, and histopathological features, including age associated changes beyond those in controls.
    Results: Motor conduction studies showed age associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve. Sensory conduction studies revealed more profound reduction of action potentials than motor studies with little age related change. Large myelinated fibre loss was seen in the sural nerve irrespective of age at examination.
    Conclusions: Irreversible axonal damage may occur at entrapment sites in motor nerves in HNPP patients, progressing with aging. Sensory nerves may show more profound axonal abnormality, but without age association. The electrophysiological features of HNPP are presumed to be a mixture of abnormalities occurring from early in life and acquired features caused by repetitive insults at entrapment sites. Unlike Charcot-Marie-Tooth disease type 1A, age associated axonal damage may not occur unless the nerves are subjected to compression.

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  • A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG) 8 repeat expansion in the PAPBN1 gene 査読

    Takayoshi Tokutake, Takeshi Ikeuchi, Keiko Tanaka, Osamu Onodera, Masatoyo Nishizawa

    Clinical Neurology45 ( 6 ) 437 - 440   2005年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1
    PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG) 8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.

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  • Clinical and electrophysiologic correlates of IVIg responsiveness in CIDP 査読

    M Iijima, M Yamamoto, M Hirayama, F Tanaka, M Katsuno, K Mori, H Koike, N Hattori, K Arimura, M Nakagawa, H Yoshikawa, K Hayasaka, O Onodera, M Baba, H Yasuda, T Saito, M Nakazato, K Nakashima, J Kira, R Kaji, N Oka, G Sobue

    NEUROLOGY64 ( 8 ) 1471 - 1475   2005年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    To identify clinical and electrophysiologic features related to IV immunoglobulin (IVIg) responsiveness in chronic inflammatory demyelinating polyneuropathy ( CIDP), the authors conducted a multicenter study on 312 patients with CIDP ( 199 responders and 113 nonresponders). Muscle atrophy and decreased compound muscle action potential were pronounced in nonresponders of IVIg. Male gender, longer disease duration, and slow progression of symptoms were also associated with IVIg unresponsiveness. Features suggesting axonal dysfunction in peripheral nerves indicated IVIg unresponsiveness in CIDP.

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  • A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease 査読

    A Ishikawa, YS Piao, A Miyashita, R Kuwano, O Onodera, H Ohtake, M Suzuki, M Nishizawa, H Takahashi

    ANNALS OF NEUROLOGY57 ( 3 ) 429 - 434   2005年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    We report early-onset parkinsonism and dementia of 18 years' duration in a 52-year-old man whose grandfather and father had suffered from a similar neurological disease. In this patient, we found neuronal loss in various brain regions including the substantia nigra and cerebral cortex, Lewy bodies, cotton wool plaques, corticospinal tract degeneration, cerebral amyloid angiopathy, and a novel three-base pair deletion in exon 12 of the presenilin-1 (PSEN1) gene. We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of a-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques.

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  • Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan 査読

    K Hara, O Onodera, M Endo, H Kondo, H Shiota, K Miki, N Tanimoto, T Kimura, M Nishizawa

    MOVEMENT DISORDERS20 ( 3 ) 380 - 382   2005年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been described in the Quebec region and in Tunisia. We report on two Japanese siblings with a new homozygous mutation (6543 del A) of the SACS gene. Compared with previously reported ARSACS patients, both of these patients had a unique phenotype characterized by dementia, ophthalmoplegia, and the absence of prominent retinal myelinated fibers. (c) 2004 Movement Disorder Society.

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  • A pedigree of Charcot-Marie-Tooth disease type 4F (Periaxin mutation) 査読

    Mitsuteru Shimohata, Kiyoshi Hirahara, Shuichi Igarashi, Kenju Hara, Kazuki Kijima, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa, Shoji Tsuji, Kiyoshi Hayasaka

    Clinical Neurology45 ( 3 ) 221 - 225   2005年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We report a 51-year-old man genetically diagnosed as Charcot-Marie-Tooth disease type 4F. The patient was the first child of healthy, consanguineous parents. He had two sisters and one of them showed similar but milder symptoms. He had gait disturbance since childhood. Then he noticed muscle weakness of his hands at the age of early forties, and more difficulties in gait at the age of late forties. On examination at age 51, he showed absence of all deep tendon reflexes, weakness of the hand and distal leg muscles, pes cavus and decreased sensitivity to touch and vibration in the lower extremities. Electrophysiological studies of the median nerve showed delayed motor nerve conduction velocity and undetectable sensory nerve action potentials. The histology of his sural nerve revealed moderate loss of large myelinated fibers and the diameters of residual fibers shifted to small shown as size-frequency histogram. Many fibers are thinly myelinated and some of the Schwann cells looked as wrapping around the myelinate fibers with their processes. On gene analyses, we identified an Arg 1070 Stop homozygous mutation in the Periaxin, known to be a causative gene for CMT type 4F. Based on these observations, we emphasized that broad genetic analyses are necessary for diagnosis of CMT disease, including so far unidentified mutations among the Japanese populations.

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  • Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation 査読

    T Takahashi, K Nozaki, S Tsuji, M Nishizawa, O Onodera

    NEUROREPORT16 ( 3 ) 295 - 299   2005年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Transcriptional dysregulation, particularly cAMP-responsive-element-mediated transcriptional repression, has been implicated in expanded polyglutamine diseases. However, it has not been clarified whether this transcriptional repression is a cause or result of neurodegeneration. Furthermore, the association between aggregates of expanded polyglutamine stretches and transcriptional repression is not clear. We established isogenic cell lines with polyglutamine stretches, which also expressed d2EGFP under the control of cAMP-responsive elements. In this system, the polyglutamine stretch repressed cAMP-responsive-element-mediated transcription without the formation of macroscopic expanded polyglutamine aggregates. Furthermore, aggregate formation did not have an adverse effect on the repression of transcriptional activity. The results demonstrated that the repression of cAMP-responsive-element-mediated transcription is an early event caused by a soluble form of polyglutamine stretch. (c) 2005 Lippincott Williams T Wilkins.

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  • Evaluation of two patients with SCA2 with frontal lobe dysfunction using brain SPECT with three-dimensional stereotactic surface projections (3D-SSP) 査読

    Takayoshi Shimohata, Yoko Matsuzawa, Koumei Tanaka, Osamu Onodera, Keiko Tanaka, Masatoyo Nishizawa

    Clinical Neurology45 ( 1 ) 22 - 26   2005年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We evaluated the cognitive impairment of two patients with genetically confirmed spinocerebellar ataxia type 2 (SCA2). Neurological examination revealed ignorance of his illness and Gegenhalten phenomenon in patient 1, and emotional incontinence in patient 2. Although their mental status evaluated by HDS-R or Mini-Mental State Examination (MMSE) was almost normal, the results of WAIS-R and Wisconsin Card Sorting Test (WCST) revealed the existence of intellectual decline and executive dysfunction. 3D-SSP SPECT demonstrated distinct hypoperfusion in bilateral frontal lobes, whereas brain MRI revealed no apparent cerebral atrophy in both patients. These results raise the possibility that frontal lobe dysfunction was observed in the early stages of SCA2, and that 3D-SSP SPECT is useful for evaluating the involvement of frontal lobe dysfunction in SCA2.

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  • The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 査読

    H Date, S Igarashi, Y Sano, T Takahashi, T Takahashi, H Takano, S Tsuji, M Nishizawa, O Onodera

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS325 ( 4 ) 1279 - 1285   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Aprataxin (APTX) is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH/AOA1). In our previous study, we found that APTX interacts with X-ray repair cross-complementing group 1 (XRCC1), a scaffold protein with an essential role in single-strand DNA break repair (SSBR). To further characterize the functions of APTX, we determined the domains of APTX and XRCC1 required for the interaction. We demonstrated that the 20 N-terminal amino acids of the FHA domain of APTX are important for its interaction with the C-terminal region (residues 492-574) of XRCC1. Moreover, we found that poly (ADP-ribose) polymerase-1 (PARP-1) is also co-immunoprecipitated with APTX. These findings suggest that APTX, together with XRCC1 and PARP-1, plays an essential role in SSBR. (C) 2004 Elsevier Inc. All rights reserved.

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  • Clinical spectrums of SCA 17 depend on length of CAA/CAG repeat units in the TBP gene. 査読

    Toyoshima Y, Yamada M, Onodera O, Shimohata M, Inenaga C, Fujita N, Morita M, Tsuji S, Takahashi H

    Annals of Neurology56   163 - 164   2004年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • beta-Synuclein gene alterations in dementia with Lewy bodies 査読

    H Ohtake, P Limprasert, Y Fan, O Onodera, A Kakita, H Takahashi, LT Bonner, DW Tsuang, IVJ Murray, VMY Lee, JQ Trojanowski, A Ishikawa, J Idezuka, M Murata, T Toda, TD Bird, JB Leverenz, S Tsuji, AR La Spada

    NEUROLOGY63 ( 5 ) 805 - 811   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Objective: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies ( DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. Conclusion: Mutations in the beta-synuclein gene may predispose to DLB.

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  • Quantitative evaluation of brainstem involvement in multiple system atrophy by diffusion-weighted MR imaging 査読

    M Kanazawa, T Shimohata, K Terajima, O Onodera, K Tanaka, S Tsuji, K Okamoto, M Nishizawa

    JOURNAL OF NEUROLOGY251 ( 9 ) 1121 - 1124   2004年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:DR DIETRICH STEINKOPFF VERLAG  

    In multiple system atrophy (MSA), symptoms associated with dysfunctions of the brainstem and autonomic nervous system are important prognostic factors. We investigated brainstem involvement in 12 patients with MSA with predominant cerebellar symptoms (MSA-C) (mean age, 56.3 +/- 9.9 years, median disease duration, 3 years), and 11 controls (57.6 +/- 12.0 years) matched for age using diffusion-weighted MR imaging (DWI). We demonstrated that apparent diffusion coefficients (ADCs) in the pons and middle cerebellar peduncle of MSA-C patients are significantly higher than those of normal controls even though the patients are in the early stage of the disease. Furthermore, we demonstrated that increased ADC values correlated well with the disease duration. The current study demonstrated that DWI is a useful noninvasive method for the quantitative evaluation of the brainstem involvement in MSA-C patients.

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  • Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin 査読

    T Shimohata, T Kimura, M Nishizawa, O Onodera, S Tsuji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY75 ( 8 ) 1206 - 1207   2004年8月

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    記述言語:英語   出版者・発行元:B M J PUBLISHING GROUP  

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  • Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5 査読

    H Ohtake, T Shimohata, K Terajima, T Kimura, R Jo, R Kaseda, O Iizuka, M Takano, Y Akaiwa, H Goto, H Kobayashi, T Sugai, T Muratake, T Hosoki, T Shioiri, K Okamoto, O Onodera, K Tanaka, T Someya, T Nakada, S Tsuji

    NEUROLOGY62 ( 9 ) 1601 - 1603   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

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  • Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity 査読

    HA Popiel, Y Nagai, O Onodera, T Inui, N Fujikake, Y Urade, WJ Strittmatter, Burke, JR, A Ichikawa, T Toda

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS317 ( 4 ) 1200 - 1206   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The polyglutamine (polyQ) diseases are a class of inherited neurodegenerative diseases including Huntington's disease, caused by the expansion of a polyQ stretch within each disease protein. This expansion is thought to cause a conformational change in the protein leading to aggregation of the protein, resulting in cytotoxicity. To analyze whether disrupting the toxic conformation of the polyQ protein can alter its aggregation propensity and cytotoxicity, we examined the effect of interruption of the expanded polyQ stretch by proline insertion, since prolines cause great alterations in protein conformation. Here, we show that insertion of prolines into the expanded polyQ stretch indeed disrupts its ordered secondary structure, leading to suppression of polyQ protein aggregation both in vitro and in cell culture, and reduction of cytotoxicity in correlation with the number of proline interruptions. Furthermore, we found that a short polyQ stretch with a proline interruption is able to inhibit aggregation of the expanded polyQ protein in trans. These results show that a gain in toxic conformation of the expanded polyQ protein is essential for aggregation and cytotoxicity, providing insight into establishing therapies against the polyQ diseases. (C) 2004 Elsevier Inc. All rights reserved.

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  • Aprataxin, a novel protein that protects against genotoxic stress 査読

    N Gueven, OJ Becherel, AW Kijas, P Chen, O Howe, JH Rudolph, R Gatti, H Date, O Onodera, G Taucher-Scholz, MF Lavin

    HUMAN MOLECULAR GENETICS13 ( 10 ) 1081 - 1093   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia, a syndrome characterized by abnormal responses to double-strand DNA breaks and genome instability. The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair. We demonstrate that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilize the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generate highly unstable products. Cells from AOA1 patients are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA but there is no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA. We also demonstrate that aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and that it co-localizes with XRCC1 along charged particle tracks on chromatin. These results demonstrate that aprataxin influences the cellular response to genotoxic stress very likely by its capacity to interact with a number of proteins involved in DNA repair.

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  • Gene diagnosis of patients with chorea 査読

    Takayoshi Shimohata, Osamu Onodera, Yoshiaki Honma, Koichi Hirota, Yasuhito Nunomura, Tetsuya Kimura, Izumi Kawachi, Kazuhiro Sanpei, Masatoyo Nishizawa, Shoji Tsuji

    Clinical Neurology44 ( 3 ) 149 - 153   2004年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    To elucidate the etiology of chorea, we performed gene diagnoses of 79 consecutive cases of the disease (34 males, 45 females
    age 15-79 years), which include 39 familial cases (37 pedigrees) and 40 sporadic cases, from 1997 to 2002, after their informed consent was obtained. We extracted genomic DNA from peripheral white blood cells, and performed genetic tests for Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), Huntington disease like 1 (HDL1), HDL2 and spinocerebellar ataxia type 17 (SCA17). We found 37 cases (36 pedigrees) of HD, seven cases (seven pedigrees) of DRPLA. No cases of HDL1, HDL2 and SCA17 were found. We also found three cases (two pedigrees) presenting an autosomal dominant trait with an unknown origin, and two cases whose parents were consanguineously related. Therefore, further genetic heterogeneity is expected in the cases of chorea in Japan.

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  • Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein 査読

    Y Sano, H Date, S Igarashi, O Onodera, M Oyake, T Takahashi, S Hayashi, M Morimatsu, H Takahashi, T Makifuchi, N Fukuhara, S Tsuji

    ANNALS OF NEUROLOGY55 ( 2 ) 241 - 249   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early-onset ataxia, ocular motor apraxia, and hypoalbuminemia. Recently, the causative gene for EAOH, APTX, has been identified. Of the two splicing variants of APTX mRNA, the short and the long forms, long-form APTX mRNA was found to be the major isoform. Aprataxin is mainly located in the nucleus, and, furthermore, the first nuclear localization signal located near the amino terminus of the long-form aprataxin is essential for its nuclear localization. We found, based on the yeast two-hybrid and coimmunoprecipitation experiments, that the long-form but not the short-form aprataxin interacts with XRCC1 (x-ray repair cross-complementing group 1). Interestingly the amino terminus of the long-form aprataxin is homologous with polynucleotidekinase-3'-phosphatase, which has been demonstrated to be involved in base excision repair, a subtype of single-strand DNA break repair, through interaction with XRCC1, DNA polymerase beta, and DNA ligase III. These results strongly support the possibility that aprataxin and XRCC1 constitute a multiprotein complex and are involved in single-strand DNA break repair, and furthermore, that accumulation of unrepaired damaged DNA underlies the pathophysiological mechanisms of EAOH.

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  • SCA17 homozygote showing Huntington's disease-like phenotype 査読

    Y Toyoshima, M Yamada, O Onodera, M Shimohata, C Inenaga, N Fujita, M Morita, S Tsuji, H Takahashi

    ANNALS OF NEUROLOGY55 ( 2 ) 281 - 286   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    We report a homozygous case of spinocerebellar ataxia type 17 with 48 glutamines. The age of the patient at disease onset was not lower than those of heterozygotes with the same CAG-repeat sizes, but the clinical manifestations were rapidly progressive dementia and chorea. Neuronal loss was relatively restricted and most prominent in the Purkinje cell layer and striatum; however, intranuclear neuronal polyglutamine accumulation was widespread, with a high frequency in the cerebral cortex and striatum.

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  • Two Cases of Generalized Tetanus Presenting with Dysphagia as an Initial Symptom 査読

    Masato Kanazawa, Hideaki Ishiguro, Osamu Onodera, Kenjiro Yoshikawa, Takashi Koide, Aki Arai, Arika Hasegawa, Ryouichi Nakano, Keiko Tanaka, Masatoyo Nishizawa

    Brain and Nerve55 ( 11 ) 973 - 976   2003年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We describe two patients with generalized tetanus, a 60-year-old man and a 76-year-old woman, presenting with dysphagia as an initial symptom of the disease. Eighty percent of patients with generalized tetanus manifest dysphagia on admission to a hospital. However, dysphagia is rare as an initial symptom. Both our patients had dysphagia as their initial symptom, followed by neck stiffness and trismus. We made a diagnosis of generalized tetanus based on these neurological findings in the absence of an apparent episode of trauma. After the administration of tetanus immunoglobulin on admission, they recovered without exhibiting generalized convulsion, autonomic storm, or any other serious complications. The vaccination of tetanus toxoid cannot maintain sufficient antibody titers more than ten years. Therefore, elderly people are considered susceptible to tetanus. We suggest that tetanus should be considered in the differential diagnosis of dysphagia particularly in elderly patients. We also suggest that treatment of tetanus should be initiated immediately, because tetanus still has a high mortality rate at present.

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  • Severe generalized dystonia as a presentation of a patient with aprataxin gene mutation 査読

    Y Sekijima, T Hashimoto, O Onodera, H Date, T Okano, K Naito, S Tsuji, S Ikeda

    MOVEMENT DISORDERS18 ( 10 ) 1198 - 1200   2003年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    A 14-year-old girl, homozygous for an insertion mutation of aprataxin (APTX), 689 ins T, is described. She presented with severe generalized dystonia, ataxia, ocular motor apraxia, and areflexia. The dystonia of this patient suggests involvement of the basal ganglia or thalamus, along with clinical diversity in this disorder. 0 2003 Movement Disorder Society.

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  • [Steroid-pulse therapy in Guillain-Barré syndrome associated with cytomegalovirus infection: a case report]. 査読

    Tada M, Onodera O, Kawachi I, Hara K, Sato M, Yoshino H, Asano A, Soma Y, Tsuji S

    No to shinkei = Brain and nerve55 ( 7 ) 615 - 621   2003年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients 査読

    N Hattori, M Yamamoto, T Yoshihara, H Koike, M Nakagawa, H Yoshikawa, A Ohnishi, K Hayasaka, O Onodera, M Baba, H Yasuda, T Saito, K Nakashima, J Kira, R Kaji, N Oka, G Sobue

    BRAIN126 ( Pt 1 ) 134 - 151   2003年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.

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  • Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene 査読

    T Takahashi, S Igarashi, T Kimura, Hozumi, I, Kawachi, I, O Onodera, H Takano, M Saito, S Tsuji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY72 ( 5 ) 676 - 677   2002年5月

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    記述言語:英語   出版者・発行元:BRITISH MED JOURNAL PUBL GROUP  

    DOI: 10.1136/jnnp.72.5.676

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  • Expanded polyglutamine stretches form an 'aggresome' 査読

    T Shimohata, A Sato, Burke, JR, WJ Strittmatter, S Tsuji, O Onodera

    NEUROSCIENCE LETTERS323 ( 3 ) 215 - 218   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    To understand the pathogenetic mechanisms underlying polyglutamine (polyQ) diseases, we investigated the mechanisms of the formation of aggregate bodies containing expanded polyQ stretches, focusing on dentatorubral-pallidoluysian atrophy (DRPLA). We demonstrated that the expression of a truncated DRPLA protein containing expanded polyQ stretches in COS-7 cells resulted in the formation of perinuclear aggregate bodies that are co-localized with gamma-tubulin, a protein marker for the microtubules-organizing center (MTOC). A collapsed vimentin network surrounded these aggregate bodies. Furthermore, disruption of the microtubules (MTs) with nocodazole resulted in the formation of small aggregate bodies that were scattered throughout the cytoplasm. These findings suggest that the truncated DRPLA proteins containing expanded polyQ stretches unfold and form small aggregate bodies in the cell periphery. These aggregates move on MTs to the MTOC, where they remain as distinct 'aggresomes'. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0304-3940(02)00162-3

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  • Time course of polyglutamine aggregate body formation and cell death: Enhanced growth in nucleus and an interval for cell death 査読

    Toyoshima, I, M Sugawara, K Kato, C Wada, T Shimohata, R Koide, O Onodera, S Tsuji

    JOURNAL OF NEUROSCIENCE RESEARCH68 ( 4 ) 442 - 448   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Polyglutamine (polyQ) aggregate bodies are a hallmark of dentatorubral-pallidoluysian atrophy and related neurodegenerative disorders, although the relationship between aggregate body formation and cell death is not clear. We analyzed the kinetics of polyQ aggregate formation and the time intervals for cell death, tracking individual cells using fluorescence video microscopy, for the first time. Expanded polyQ tracts of atrophin-1 with or without nuclear localization signal (NLS) labeled with green fluorescent protein (GFP) were constructed, Q57NLS/GFP and Q56/GFP, respectively. All of the Q57NLS/GFP aggregate bodies were in nuclei, and all of the Q56/GFP aggregate bodies were in cytoplasm. Aggregates of Q56/GFP were larger than those of Q57NLS/ GFP. Surprisingly, a kinetic analysis showed that the latter grew 5.37 times faster than the former. The time interval between transfection and cell death was shorter in Q57NLS/GFP, but the time between the end of the rapid growing phase of aggregation and the start of the cell death process did not show a significant difference. Aggregate growth was confirmed to correspond to the accumulated free polyQ by the time of starting aggregation. These findings suggest that aggregate body formation induced by expanded polyQ stretches is a self-limiting process and is enhanced by factor(s) in nuclei, whereas it is not tightly bound to the cell death process. (C) 2002 Wiley-Liss,

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  • Epidemiology of X-linked adrenoleukodystrophy in Japan 査読

    Y Takemoto, Y Suzuki, A Tamakoshi, O Onodera, S Tsuji, T Hashimoto, N Shimozawa, T Orii, N Kondo

    JOURNAL OF HUMAN GENETICS47 ( 11 ) 590 - 593   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER-VERLAG TOKYO  

    To clarify the epidemiology of X-linked adrenoleukodystrophy (ALD) in Japan, we performed a questionnaire survey. Two hundred eighty-six patients, including 154 from internal medicine, 100 from pediatrics, 21 from psychiatry, and I I from other hospitals, were reported to have ALD between 1990 and 1999. The data on 154 patients revealed the phenotypic distribution to be as follows: childhood cerebral form (29.9%), adrenomyeloneuropathy (25.3%), adult cerebral form (21.4%), adolescent form (9.1%), olivo-ponto-cerebellar form (8.4%), presymptomatic form (4.5%), and symptomatic female patient (1.3%). The adult cerebral form and olivo-ponto-cerebellar form were more common in Japan than in North America and Europe. The incidence of X-linked ALD in Japan was estimated to be between 1: 30 000 and 1: 50 000 boys, similar to previous reports. About half of the patients with adrenomyeloneuropathy and the olivo-ponto-cerebellar phenotype developed cerebral involvement with a mean interval of 8.2 and 2.2 years after ALD onset, respectively. The family histories revealed that brothers and first cousins tended to show similar phenotypes, whereas nephews tended to develop symptoms earlier than uncles. These data will help in understanding the natural history of X-linked ALD.

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  • Paraneoplastic striatal encephalitis 査読

    T Oguma, H Kobayashi, S Katada, O Onodera, K Tanaka, S Tsuji, T Uno, T Ishida, H Kagamu, F Gejyo, M Motomura

    NEUROLOGY57 ( 12 ) 2326 - 2326   2001年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene 査読

    H Date, O Onodera, H Tanaka, K Iwabuchi, K Uekawa, S Igarashi, R Koike, T Hiroi, T Yuasa, Y Awaya, T Sakai, T Takahashi, H Nagatomo, Y Sekijima, Kawachi, I, Y Takiyama, M Nishizawa, N Fukuhara, K Saito, S Sugano, S Tsuji

    NATURE GENETICS29 ( 2 ) 184 - 188   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE AMERICA INC  

    Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs(1-4). We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus(5). We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

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  • Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation 査読

    K Nozaki, O Onodera, H Takano, S Tsuji

    NEUROREPORT12 ( 15 ) 3357 - 3364   2001年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Expanded polyglutamine stretches have been shown to form aggregates and to be toxic to cells. In this study, we hypothesized that amino acid sequences flanking the polyglutamine stretches influence the aggregate formation potential of these stretches. Green fluorescent protein (GFP) fusion proteins containing glutamine repeats of various lengths and a fixed number of flanking amino acids of ataxin-2, huntingtin, clentatorubral-pallidoluysian atrophy protein (DRPLAP) or ataxin-3 were transiently expressed in COS-7 cells. The aggregate formation potential of ataxin-2 and DRPLAP increased in a CAG-repeat-length-dependent manner, with a threshold between 34 and 36. Truncated ataxin-2-Q56-GFP and truncated huntingtin-Q56-GFP showed a significantly higher aggregate formation potential than truncated DRPLAP-Q56-GFP or truncated ataxin-3-Q56-GFP. These results are in agreement with the clinical observation that ages of disease onset in patients with spinocerebellar ataxia type 2 or Huntington's disease are lower than those in patients with DRPLA or Machado-Joseph disease having expanded CAG repeats of the same length. Furthermore, mutagenesis of the flanking sequence of ataxin-2 markedly reduced its aggregate formation potential. These results indicate that the amino acid sequences flanking the polyglutamine stretches significantly influence their aggregate formation potential. NeuroReport 12:3357-3364 (C) 2001 Lippincott Williams & Wilkins.

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  • Expanded polyglutamine stretches lead to aberrant transcriptional regulation in polyglutamine diseases. 査読

    Shimohata T, Onodera O, Tsuji S

    Human cell14 ( 1 ) 17 - 25   2001年3月

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  • Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases 査読

    T Shimohata, O Onodera, S Tsuji

    NEUROPATHOLOGY20 ( 4 ) 326 - 333   2000年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL SCIENCE ASIA  

    At least eight inherited neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. The nuclear translocation of mutant proteins containing expanded polyQ stretches has been demonstrated as a prerequisite for the expression of their cytotoxicity. Hypothesizing that nuclear proteins that interact with mutant proteins, particularly, those that bind to the expanded polyQ stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, nuclear proteins were screened for their capability of binding to expanded polyQ stretches. It was found that expanded polyQ stretches preferentially bind to TAF(II)130, a coactivator involved in cAMP-responsive element-binding protein (CREB)-dependent transcriptional activation. The binding of TAF(II)130 with expanded polyQ stretches strongly suppresses CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF(II)130 and redistribution of TAF(II)130 are involved in the pathogenetic mechanisms underlying neurodegeneration.

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  • Expanded polyglutamine stretches interact with TAF(II)130, interfering with CREB-dependent transcription 査読

    T Shimohata, T Nakajima, M Yamada, C Uchida, O Onodera, S Naruse, T Kimura, R Koide, K Nozaki, Y Sano, H Ishiguro, K Sakoe, T Ooshima, A Sato, T Ikeuchi, M Oyake, T Sato, Y Aoyagi, Hozumi, I, T Nagatsu, Y Takiyama, M Nishizawa, J Goto, Kanazawa, I, Davidson, I, N Tanese, H Takahashi, S Tsuji

    NATURE GENETICS26 ( 1 ) 29 - 36   2000年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded! polyQ stretches preferentially bind to TAF(II)130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAF(II)130. Our results indicate that interference of transcription by the binding of TAF(II)130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

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  • Mutational Analysis of X-Linked Adrenoleukodystrophy Gene 査読

    Hiroki Takano, Ryoko Koike, Osamu Onodera, Shoji Tsuji

    Cell Biochemistry and Biophysics32   177 - 185   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Humana Press  

    X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder characterized by progressive neurological dysfunction, occasionally associated with adrenal insufficiency. The clinical phenotypes of ALD are quite variable, and include childhood ALD, adult-onset ALD, adrenomyeloneuropathy, and Addison's disease only. Although the causative gene for ALD has been identified, the physiological role of the gene product remains to be clarified. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified. The authors investigated genotype-phenotype correlatons in ALD by analyses on 29 unrelated Japanese patients with ALD and by a review of the literature. All the phenotypes were associated with mutations leading to protein truncation, as well as those resulting in subtle amino acid changes. Furthermore, there were no differences in phenotypic expression among the natures of the subtle amino acid changes. All these data indicate that no obvious correlations exist between the phenotypes of ALD patients and their geneotypes, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD.

    DOI: 10.1385/CBB:32:1-3:177

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  • No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy 査読

    T Ozawa, H Takano, O Onodera, H Kobayashi, T Ikeuchi, R Koide, K Okuizumi, T Shimohata, K Wakabayashi, H Takahashi, S Tsuji

    NEUROSCIENCE LETTERS270 ( 2 ) 110 - 112   1999年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    To determine whether mutations in the coding region of the alpha-synuclein gene are relevant in cases of multiple system atrophy (MSA), detailed nucleotide sequence analysis of the alpha-synuclein gene was performed using total RNA obtained from autopsied brain specimens of 11 pathologically confirmed cases of MSA. The brain specimens used in this study contained both gray and white matter, which were dissected from the frontal, temporal or occipital lobe. No nucleotide alterations were found in the entire coding region of the alpha-synuclein gene in any of the cases. While mutations In the regulatory or intronic regions of the gene were not ruled out, our results suggest that mutations in the coding region of the alpha-synuclein gene are unlikely to contribute to the pathogenesis of MSA. (C) 1999 Elsevier Science ireland ltd. All rights reserved.

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  • Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy 査読

    H Takano, R Koike, O Onodera, R Sasaki, S Tsuji

    ARCHIVES OF NEUROLOGY56 ( 3 ) 295 - 300   1999年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER MEDICAL ASSOC  

    Background: X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of AID usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated.
    Objectives: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients.
    Methods: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes.
    Results: Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene, Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMF70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12-17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids.
    Conclusion: There are no obvious correlations be tween the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.

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  • Expanded polyglutamine domain proteins bind neurofilament and alter the neurofilament network 査読

    Y Nagai, O Onodera, J Chun, WJ Strittmatter, Burke, JR

    EXPERIMENTAL NEUROLOGY155 ( 2 ) 195 - 203   1999年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC  

    Eight inherited neurodegenerative diseases are caused by genes with expanded CAG; repeats coding for polyglutamine domains in the disease-producing proteins. The mechanism by which this expanded polyglutamine domain causes neurodegenerative disease is unknown, but nuclear and cytoplasmic polyglutamine protein aggregation is a common feature. In transfected COS7 cells, expanded polyglutamine proteins aggregate and disrupt the vimentin intermediate filament network. Since neurons have an intermediate filament network composed of neurofilament (NF) and NF abnormalities occur in neurodegenerative diseases, we examined whether pathologic-length polyglutamine domain proteins also interact with NF. We expressed varying lengths polyglutamine-green fluorescent protein fusion proteins in a neuroblast cell line, TR1. Pathologic-length polyglutamine-GFP fusion proteins formed large cytoplasmic aggregates surrounded by neurofilament. Immunoisolation of pathologic-length polyglutamine proteins coisolated 68-kDa NF protein demonstrating molecular interaction. These observations suggest that polyglutamine interaction with NF is important in the pathogenesis of the polyglutamine repeat diseases. (C) 1999 Academic Press.

    DOI: 10.1006/exnr.1998.6991

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  • Generation of neuronal intranuclear inclusions by polyglutamine-GFP: Analysis of inclusion clearance and toxicity as a function of polyglutamine length 査読

    KL Moulder, O Onodera, Burke, JR, WJ Strittmatter, EM Johnson

    JOURNAL OF NEUROSCIENCE19 ( 2 ) 705 - 715   1999年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Recent evidence suggests that, in huntingtin and many other proteins, polyglutamine repeats are a toxic stimulus in neurodegenerative diseases. To investigate the mechanism by which these repeats may be toxic, we transfected primary rat cerebellar granule neurons with polyglutamine-green fluorescent protein (GFP) fusion constructs containing 19 (Q19-GFP), 35 (Q35-GFP), 56 (Q56-GFP), or 80 (Q80-GFP) glutamine residues. All constructs, except Q19-GFP, aggregated within the nuclei of transfected cells in a length- and time-dependent manner. Although Q35-GFP expression led to the development of several small aggregates per cell, these aggregates were cleared or degraded, and the cells remained viable. In contrast, Q80-GFP expression resulted in one or two large aggregates and induced cell death. Caspase activation was observed after Q80-GFP aggregation, but inhibition of caspases with Boc-aspartyl-(OMe)-fluoromethylketone (BAF) only served to delay, not prevent, toxicity. In addition, aggregation and toxicity were not affected by other modulators of neuronal cell death such as genetic deletion of the proapoptotic bcl-2 family member bax or addition of the protein synthesis inhibitor cycloheximide. Lastly, nuclear condensation did not occur as part of the toxicity. These data suggest that polyglutamine-GFP expression is toxic to primary neurons but that the death is distinct from classical apoptosis.

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  • Polyglutamine domain proteins with expanded repeats bind neurotilament, altering the neurofilament network 査読

    Y Nagai, O Onodera, WJ Strittmatter, Burke, JR

    OXIDATIVE/ENERGY METABOLISM IN NEURODEGENERATIVE DISORDERS893   192 - 202   1999年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NEW YORK ACAD SCIENCES  

    Proteins with expanded polyglutamine (polyQ) repeats cause eight inherited neurodegenerative diseases, Nuclear and cytoplasmic polyQ protein is a common feature of these diseases, but its role in cell death remains debatable. Since the neuronal intermediate filament network is composed of neurofilament (NF) and NF abnormalities occur in neurodegenerative diseases, we examined whether pathologic-length polyQ domain proteins interact with NF. me expressed polyQ-green fluorescent fusion proteins (GFP) in a neuroblast cell line, TR1. Pathologic-length polyQ-GFP fusion proteins form large cytoplasmic aggregates surrounded by neurofilament, Immunoisolation of pathologic-length polyQ proteins co-isolated 68 kD NF protein demonstrating molecular interaction. These observations suggest that polyQ interaction with NF is important in the pathogenesis of the polyglutamine repeat disease.

    DOI: 10.1111/j.1749-6632.1999.tb07826.x

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  • Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients 査読

    Toshiya Sato, Mutsuo Oyake, Kenji Nakamura, Kazuki Nakao, Yoshimitsu Fukusima, Osamu Onodera, Shuichi Igarashi, Hiroki Takano, Koki Kikugawa, Yoshinori Ishida, Takayoshi Shimohata, Reiji Koide, Takeshi Ikeuchi, Hajime Tanaka, Naonobu Futamura, Ryusuke Matsumura, Tetsuya Takayanagi, Fumiaki Tanaka, Gen Sobue, Osamu Komure, Mie Takahashi, Akira Sano, Yaeko Ichikawa, Jun Goto, Ichiro Kanazawa, Motoya Katsuki, Shoji Tsuji

    Human Molecular Genetics8 ( 1 ) 99 - 106   1999年

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    掲載種別:研究論文(学術雑誌)  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing number of hereditary neurodegenerative diseases determined as being caused by unstable expansion of CAG repeats coding for polyglutamine stretches. To investigate the molecular mechanisms underlying CAG repeat instability, we established three transgenic lines each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism which occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues including the cerebrum, consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described in this study exhibited age-dependent intergenerational as well as somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and are therefore expected to serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats.

    DOI: 10.1093/hmg/8.1.99

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  • Efficacy of early plasmapheresis in Bickerstaff's encephalitis 査読

    T Ozawa, O Onodera, T Inuzuka, Y Soma, S Tsuji

    INTERNAL MEDICINE37 ( 11 ) 986 - 989   1998年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Double filtration plasmapheresis (DFPP) was performed in a patient with Bickerstaff's brainstem encephalitis (BBE) in its early phase. He was a 27-year-old male patient suffering from diplopia, facial palsy and drowsiness following upper respiratory tract infection, and had high titers of immunoglobulin G (IgG) antibodies against ganglioside NeuAc alpha 2-8NeuAc alpha 2-3Gal beta 1-3GalNAc beta 1-4(NeuAc alpha 2-8NeuAc alpha 2-3)Gal beta 1-4Glc beta 1-1'Cer (GQ1b) in the serum, DFPP effected immediate improvement of his drowsiness, supporting the diagnosis of BBE, Our observations suggest that DFPP during the early phase of BBE efficiently prevents the progression of consciousness disturbances.

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  • A Japanese family with adrenoleukodystrophy with a codon 291 deletion: A clinical, biochemical, pathological, and genetic report 査読

    S Kano, M Watanabe, M Kanai, R Koike, O Onodera, S Tsuji, K Okamoto, M Shoji

    JOURNAL OF THE NEUROLOGICAL SCIENCES158 ( 2 ) 187 - 192   1998年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    We report a Japanese family with adrenoleukodystrophy (ALD) with a three base pair deletion (delGAG291) in the ALD gene. A variety of phenotypes were observed within this family. While the proband (patient 1) was classified as having a rare intermediate type of adult cerebral and cerebello-brain stem forms, his younger brother (patient 2) and nephew (patient 3) had a childhood ALD type. Another nephew (patient 4) of patient 1 was classified as having an adolescent form. The tau level in the cerebrospinal fluid (CSF) in patient 1 was as high as that of patients with Alzheimer's disease (AD). His brain magnetic resonance image (MRI) showed abnormalities in the bilateral cerebellar hemispheres and brain stem, but not in the cerebral white matter, where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography (PET). In patients 2 and 3, the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U-fibers, compatible with the findings of childhood ALD. Oleic and erucic acids (Lorenzo's Oil) were administered to patients 1 and 4, but sufficient effectiveness was not obtained. The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations. Moreover, although the scale of the study is limited, there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram (CT) or MRI analysis, and that the higher level of tau reflects the process of neuronal degeneration in ALD. Lorenzo's Oil should be given in the early stage. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0022-510X(98)00120-8

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  • Molecular cloning, structural organization, sequence, chromosomal assignment, and expression of the mouse alpha-N-acetylgalactosaminidase gene 査読

    T Herrmann, D Schindler, H Tabe, O Onodera, S Igarashi, A Polack, D Zehnpfennig, S Tsuji

    GENE211 ( 2 ) 205 - 214   1998年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Alpha-N-acetylgalactosaminidase (2-acetamido-2-deoxy-alpha-D-galactoside acetamidodeoxy-galactohydrolase, NAGA; EC 3.2.1.49) deficiency is a recently recognized autosomal recessive lysosomal disease. As a prerequisite for the generation of an animal model, the mouse NAGA gene was cloned and characterized. The NAGA gene was assigned to mouse chromosome 15 band E3, syntenic to the region encompassing the human gene, and NAGA-deficient mutant human cells transfected with the cosmid clone containing the mouse NAGA gene expressed NAGA activity. Comparison of the mouse NAGA nucleotide sequence with the human NAGA sequence predicted that the mouse NAGA gene contains an open reading frame of 1245 bp, comprising nine coding exons and spanning a genomic region of 8258 bp, and a 3' untranslated region of 0.5 kb. The 5' untranslated region was determined in primer extension studies to be 235 bp in length. Nucleotide identity between the human and mouse NAGA exons ranged from 67.4 to 89.5%, with better matches for exons 1-7 than for 8 and 9. The overall amino acid identity between the mouse and human deduced NAGA polypeptides was 82.0%, between those of mouse and chicken 72.9%. Homology was found to only one other mouse gene, i.e. the a-galactosidase A (GALA; EC 3.2.1.22) gene. The amino acid identity ranged from 51.6 to 62.1% in the polypeptide regions corresponding to NAGA exons 2-7 and GALA exons 1-6, but little, if any, in the remainder. These analyses gave emphasis to the strong conservation of the NAGA gene and its origin from an ancestor common with the GALA gene, with NAGA exons 8 and 9 and GALA exon 7 being the most divergent regions in the evolution of the two genes. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S0378-1119(98)00103-6

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  • Apolipoprotein E epsilon 4 allele and progression of cortical Lewy body pathology in Parkinson's disease 査読

    K Wakabayashi, A Kakita, S Hayashi, K Okuizumi, O Onodera, H Tanaka, A Ishikawa, S Tsuji, H Takahashi

    ACTA NEUROPATHOLOGICA95 ( 5 ) 450 - 454   1998年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER VERLAG  

    To elucidate whether the apolipoprotein E epsilon 4 allele (APOE4) affects cortical neuropathology in Parkinson's disease (PD), we determined APOE genotypes and quantified the densities of cortical Lewy bodies (LBs), amyloid plaques and neurofibrillary tangles in 22 autopsy-proven PD cases (12 with dementia; 10 without dementia) that were not accompanied by Alzheimer's disease. The APOE4 frequency in the demented patient group was 0.21, which was significantly higher than that in Japanese controls (P &lt; 0.04). LB densities in demented PD patients were significantly higher than those in non-demented PD patients, despite the shorter disease duration in the former. Moreover, plaque density in the temporal cortex and LB density in the cingulate cortex were significantly higher in the group with APOE4 than in that without the allele. There was no difference in tangle density between these two groups. These results suggest that APOE4 may influence the increase in the number of cortical LBs and amyloid plaques in PD. It is possible that when PD occurs in individuals with APOE4 concomitantly evolving cortical LB pathology in a proportion of cases results in limbic (transitional) or neocortical-type LB disease.

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  • Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease 査読

    O Onodera, J Idezuka, S Igarashi, Y Takiyama, K Endo, H Takano, M Oyake, H Tanaka, T Inuzuka, T Hayashi, T Yuasa, J Ito, T Miyatake, S Tsuji

    ANNALS OF NEUROLOGY43 ( 3 ) 288 - 296   1998年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia associated to varying degrees with pyramidal signs, extrapyramidal signs, or peripheral amyotrophy. It is caused by unstable expansion of the CAG repeat in the MJD1 gene on chromosome 14q32.1. To determine how the neurodegenerative process in the central nervous system of patients with MJD correlates with the size of expanded CAG repeats in the MJD1 gene and other factors, we performed detailed quantitative analyses of findings of magnetic resonance imaging of the central nervous system of 21 patients with MJD of various ages and with various sizes of expanded CAG repeats. We found that atrophy of the brainstem and cerebellar vermis in MJD patients is closely correlated not only with the size of expanded CAG repeat in the MJD1 gene but also with patient age, which suggests that the neurodegenerative process in MJD is regulated by the size of expanded CAG repeats as well as by the patient age.

    DOI: 10.1002/ana.410430305

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  • A case of chronic enteroviral meningitis and hydrocephalus associated with Bruton type agammaglobulinemia 査読

    Tetsutaro Ozawa, Osamu Onodera, Osamu Iizuka, Yoshinori Tanno, Ikuyo Eguchi, Yoshiaki Soma, Shoji Tsuji

    Brain and Nerve50 ( 2 ) 191 - 196   1998年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We report a 10-year-old boy with chronic enteroviral meningitis associated with agammaglobulinemia (CEMA) and hydrocephalus. He was treated with a low-dose intravenous administration (100 mg/kg/4 weeks) of gammaglobulin (γ-gl) since he was diagnosed as having Bruton type agammaglobulinemia at 1 year of age. At this admission, neurological examination revealed meningeal signs, Babinski sign, frontal signs, urinary incontinence, and mental retardation (IQ=48) which was considered to be a sequela of the enteroviral encephalitis which had occurred in his first year of life. T1-weighted MR imaging of the brain following gadolinium administration revealed a marked dilatation of the lateral ventricles and dense enhancement of the meninges. Enterovirus was detected in the cerebrospinal fluid (CSF) using tissue culture. Histological examination of a biopsied leptomeningeal specimen revealed inflammatory thickening, which was a likely cause of the obstruction to the flow of CSF. The hydrocephalus in this patient was treated with external drainage of CSF from the lateral ventricle. The CEMA was brought into remission by means of the intraventricular administration of γ-gl, at a dose of 125-250 mg/week (total dose: 1.5 g/8 weeks), in addition to the high dose intravenous administration (400 mg/kg/4 weeks) of γ-gl. Because of the poor prognosis of patients with CEMA, the intraventricular administration of γ-gl should be initiated immediately following a diagnosis of enteroviral meningitis.

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  • Pick's disease: selective occurrence of apolipoprotein E-immunoreactive Pick bodies in the limbic system 査読

    S Hayashi, K Wakabayashi, K Iwanaga, A Kakita, K Seki, M Tanaka, K Okuizumi, O Onodera, H Tanaka, S Tsuji, H Takahashi

    ACTA NEUROPATHOLOGICA95 ( 1 ) 1 - 4   1998年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER VERLAG  

    We carried out immunohistochemical examination of apolipoprotein E (apoE) in brains from two patients with Pick's disease. In these cases 1 and 2, the APOE genotypes were epsilon 3/4 and epsilon 3/3, respectively. In both cases, numerous argyrophilic globular intraneuronal inclusions, Pick bodies (PBs), were distributed widely throughout the brain, and immunohistochemically were occasionally positive for apoE. Interestingly, such apoE-immunoreactive PBs were virtually restricted to neurons in the limbic system; in the dentate gyrus, the proportion of apoE-immunoreactive PBs relative to the total number of argyrophilic PBs was 5.0% in case 1 and 2.7% in case 2, whereas in the frontal and temporal neocortices it was less than 0.1% in both cases. Diffuse cytoplasmic immunoreactivity for apoE was found in only a few limbic system neurons without PBs in both cases. In conclusion, it is considered that apoE may not be positively involved in the process of PB formation and that the preferential distribution of apoE-immunoreactive PBs in the limbic system may reflect the presence of certain regional factors associated with the synthesis or metabolism of apoE in this particular system.

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  • Inhibition of α-ketoglutarate-and pyruvate dehydrogenase complexes in E. coli by a glutathione S-transferase containing a pathological length poly-Q domain: A possible role of energy deficit in neurological diseases associated with poly-Q expansions? 査読

    Cooper AJ, Sheu KF, Burke JR, Onodera O, Strittmatter WJ, Roses AD, Blass JP

    Age21 ( 1 ) 25 - 30   1998年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11357-998-0004-x

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  • Prevertebral abscesses with a protracted insidious clinical course and subsequent lethal, acute pyogenic meningitis and septic shock 査読

    Tetsutaro Ozawa, Osamu Onodera, Akiyoshi Kakita, Kenju Aoki, Keiko Tanaka, Yoshiaki Soma, Hitoshi Takahashi, Shoji Tsuji

    Brain and Nerve50 ( 1 ) 75 - 79   1998年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    This report concerns a 66-year-old man suffering from prevertebral abscesses with a protracted insidious clinical course and subsequent lethal and acute pyogenic meningitis. The patient had a three-month history of mild neck pain, and died as a result of septic shock due to staphylococcus aureus (methicillin-susceptible) infection two days after admission to the hospital. At autopsy, abscesses encapsulated by fibrous connective tissue were found on the ventral surfaces of the cervical and thoracic regions of the spine. The prevertebral abscess on the upper cervical region was organized with dense fibrous tissue and contained a small number of inflammatory cells. On the other hand, the prevertebral abscess on the thoracic region was purulent and contained numerous inflammatory cells, macrophages and gram-positive cocci. Pyogenic spondylitis and discitis accompanying the prevertebral abscesses were multiple and widespread. These features suggested that the abscesses developed initially on the cervical region, extended caudally through the prevertebral space, directly involving the corpus vertebrae and discs, and ultimately caused sepsis. It is important to note that prevertebral abscesses can exhibit a protracted clinical course with only mild symptom such as minor neck pain and then manifest abruptly as acute meningitis and sepsis.

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  • Atrophy of the cerebellum and brainstem in dentatorubral pallidoluysian atrophy - Influence of CAG repeat size on MRI findings 査読

    R Koide, O Onodera, T Ikeuchi, R Kondo, H Tanaka, S Tokiguchi, A Tomoda, T Miike, F Isa, H Beppu, N Shimizu, Y Watanabe, Y Horikawa, T Shimohata, K Hirota, A Ishikawa, S Tsuji

    NEUROLOGY49 ( 6 ) 1605 - 1612   1997年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    To elucidate how the size of the expanded CAG repeat of the gene for dentatorubral pallidoluysian atrophy (DRPLA) and other factors affect the atrophy of the brainstem and cerebellum, and the appearance of high-intensity signals on T2-weighted MRI of the cerebral white matter of patients with DRPLA, we quantitatively analyzed the MRI findings of 26 patients with DRPLA, the diagnosis of which was confirmed by molecular analysis of the DRPLA gene. When we classified the patients into two groups based on the size of the expanded CAG repeat of the DRPLA gene (group 1, number of CAG repeat units greater than or equal to 66; group 2, number of CAG repeat units less than or equal to 65), we found strong inverse correlations between the age at MRI and the areas of midsagittal structures of the cerebellum and brainstem in group 1 but not in group 2. Multiple regression analysis, however, revealed that both the patient's age at MRI and the size of the expanded CAG repeat correlated with the areas of midsagittal structures. Involvement of the cerebral white matter as detected on T2-weighted images was observed more frequently in patients belonging to group 2 than in group 1 patients. Furthermore it was demonstrated that high-intensity signals can be detected on T2-weighted images of the cerebral white matter of patients with a largely expanded CAG repeat (group I) in their thirties. These results suggest that patient age as well as the size of the expanded CAG repeat are related to the degree of atrophy of the brainstem and cerebellum, and the white matter changes in patients with DRPLA.

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  • Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length 査読

    AJL Cooper, KFR Sheu, Burke, JR, O Onodera, WJ Stritmatter, AD Roses, JP Blass

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA94 ( 23 ) 12604 - 12609   1997年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (a) domains within the expressed proteins. Generally, in clinically affected individuals n greater than or equal to 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Q(n) disease proteins, but the significance of this interaction is unknown. We now report that purified glyceraldehyde 3-phosphate dehydrogenase is inactivated by tissue transglutaminase in the presence of glutathione S-transferase constructs containing a a domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Q(n) domains (n = 0 or 10). Purified cr-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length a domains (n = 62 or 81). The results suggest that tissue transglutaminase-catalyzed covalent linkages involving the larger poly-Q domains may disrupt cerebral energy metabolism in CAG/Q(n) expansion diseases.

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  • Oligomerization of expanded-polyglutamine domain fluorescent fusion proteins in cultured mammalian cells 査読

    O Onodera, Burke, JR, SE Miller, S Hester, S Tsuji, AD Roses, WJ Strittmatter

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS238 ( 2 ) 599 - 605   1997年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    Six inherited neurologic diseases, including Huntington's disease, result from the expansion of a CAG domain of the disease genes to produce a domain of more than 40 glutamines in the expressed protein. The mechanism by which expansion of this polyglutamine domain causes disease is unknown. Recent studies demonstrated oligomerization of polyglutamine-domain proteins in mammalian neurons. To study oligomerization of polyglutamine proteins and to identify heterologous protein interactions, varying length polyglutamine-green fluorescent protein fusion proteins were expressed in cultured COS-7 cells. The 19- and 35-glutamine fusion proteins (non-pathologic length) distributed diffusely throughout the cytoplasm. In contrast, 56- and 80-glutamine fusion proteins (pathologic length) formed fibrillar arrays resembling those previously observed in neurons in Huntington's disease and in a transgenic mouse model. These aggregates were intranuclear and intracytoplasmic. Intracytoplasmic aggregates were surrounded by collapsed intermediate filaments, The intermediate filament protein vimentin co-immunoisolated with expanded polyglutamine fusion proteins. This cellular model will expedite investigations into oligomerization of polyglutamine proteins and their interactions with other proteins. (C) 1997 Academic Press.

    DOI: 10.1006/bbrc.1997.7337

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  • Polyglutamine domains are substrates of tissue transglutaminase: Does transglutaminase play a role in expanded CAG/poly-Q neurodegenerative diseases? 査読

    AJL Cooper, KFR Sheu, Burke, JR, O Onodera, WJ Strittmatter, AD Roses, JP Blass

    JOURNAL OF NEUROCHEMISTRY69 ( 1 ) 431 - 434   1997年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    Huntington's disease and six other neurodegenerative diseases are associated with abnormal gene products containing expanded polyglutamine (poly-Q; Q(n)) domains (n &gt; 40). in the present work, we show that glutathione S-transferase (GST) fusion proteins containing a small, physiological-length poly-Q domain (GSTQ(10)) or a large, pathological-length poly-Q domain (GSTQ(62)) are excellent substrates of guinea pig liver (tissue) transglutaminase and that both GSTQ(10) and GSTQ(62) are activators of tissue transglutaminase-catalyzed hydroxaminolysis of N-alpha-carbobenzoxyglutaminylglycine. The present findings have implications for understanding the pathophysiological mechanisms of expanded CAG/poly-Q domain diseases.

    DOI: 10.1046/j.1471-4159.1997.69010431.x

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  • Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy (DRPLA) cDNA: Strong conservation of a polymorphic CAG repeat in the murine gene 査読

    M Oyake, O Onodera, T Shiroishi, H Takano, Y Takahashi, R Kominami, K Moriwaki, T Ikeuchi, S Igarashi, H Tanaka, S Tsuji

    GENOMICS40 ( 1 ) 205 - 207   1997年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    DOI: 10.1006/geno.1996.4522

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  • Changes in anti-HuD antibody titers in the long-term course in paraneoplastic sensory neuropathy 査読

    Y Yagi, T Inuzuka, K Takada, R Nakano, Hozumi, I, H Yoshimoto, O Onodera, K Tanaka, S Sato, M Takahashi

    EUROPEAN NEUROLOGY37 ( 2 ) 122 - 123   1997年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    DOI: 10.1159/000117422

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  • Toxicity of expanded polyglutamine-domain proteins in Escherichia coli 査読

    O Onodera, AD Roses, S Tsuji, JM Vance, WJ Strittmatter, Burke, JR

    FEBS LETTERS399 ( 1-2 ) 135 - 139   1996年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Five neurodegenerative diseases are caused by proteins with expanded polyglutamine domains. Toxicity of these proteins has been previously identified only in mammals, and no simple model systems are available. In this paper, we demonstrate in E. coli that long polyglutamine domains (59-81 residues) as GST-fusion proteins inhibit growth while smaller glutamine (10-35 residues) or polyalanine (61 residues) domains have no effect. Analogously in humans, polyglutamine repeats less than 35-40 glutamines produce a normal phenotype, while expansion greater than 40 glutamines is always associated with disease. Expression of polyglutamine proteins in E. coli may help identify the molecular mechanism of pathogenesis of CAG trinucleotide repeat diseases and be a useful screen to identify potential therapeutic compounds.

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  • Lack of association of very low density lipoprotein receptor gene polymorphism with Caucasian Alzheimer's disease 査読

    K Okuizumi, O Onodera, K Seki, H Tanaka, Y Namba, K Ikeda, AM Saunders, MA PericakVance, AD Roses, S Tsuji

    ANNALS OF NEUROLOGY40 ( 2 ) 251 - 254   1996年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LITTLE BROWN CO  

    To determine whether the association of the very low density lipoprotein receptor (VLDL-R) gene with Alzheimer's disease (AD), which has recently been identified in Japanese AD patients, is commonly observed in AD patients of other ethnic backgrounds, we have investigated the allele frequency of the polymorphic CGG repeat in the 5'-UTR of the VLDL-R gene using a data set of 84 caucasian AD patients with 104 caucasian controls. Although the allele frequency of the 8-repeat allele was slightly lower, and that of 9-repeat allele was slightly higher, in the caucasian AD patients than in caucasian controls, the differences were not statistically significant. Multiple logistic regression analysis using apolipoprotein E4 (APOE4) allele, 5-, 8-, or 9-repeat allele of the VLDL-R gene, sex, and age at onset as the predictors revealed that only the APOE4 allele was significantly associated with AD in the data set of the caucasian AD patients and controls.

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  • Association study between schizophrenia and dopamine D3 receptor gene polymorphism 査読

    T Tanaka, S Igarashi, O Onodera, H Tanaka, M Takahashi, M Maeda, K Kameda, S Tsuji, S Ihda

    AMERICAN JOURNAL OF MEDICAL GENETICS67 ( 4 ) 366 - 368   1996年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Crocq et al, [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a Ball polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene, In response to this report, further studies were conducted; however, these studies yielded conflicting results, In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia, Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls, Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset, A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes, Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist. (C) 1996 Wiley-Liss, Inc.

    DOI: 10.1002/(SICI)1096-8628(19960726)67:4<366::AID-AJMG9>3.0.CO;2-K

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  • Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: Cellular population-dependent dynamics of mitotic instability 査読

    H Takano, O Onodera, H Takahashi, S Igarashi, M Yamada, M Oyake, T Ikeuci, R Koide, H Tanaka, K Iwabuchi, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS58 ( 6 ) 1212 - 1222   1996年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:UNIV CHICAGO PRESS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by unstable expansion of a CAG repeat in the DRPLA gene. We performed detailed quantitative analysis of the size and the size distribution (range) of the expanded CAG repeats in various regions of the CNS of eight autopsied patients with DRPLA. Expanded alleles (AE) showed considerable variations in size, as well as in range, depending on the region of the CNS, whereas normal alleles did not show such variations, which indicates the occurrence of somatic mosaicism of AE in the CNS. The AE in the cerebellar cortex were consistently smaller by two to five repeat units than those in the cerebellar white matter. Moreover, the AE in the cerebral cortex were smaller by one to four repeat units than those in the cerebral white matter. These results suggest that the smaller AE in the cerebellar and cerebral cortices represent those of neuronal cells. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter showed considerable variation ranging from 9 to 23 repeat units, whereas those in the cerebellar cortex showed little variance and were similar to 7 repeat units. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter were much broader in patients with higher ages at death than they were in patients with lower ages at death, raising the possibility that the range of AE increases with time, as the result of mitotic instability of AE.

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  • Non-Mendelian transmission in Dentatorubral-Pallidoluysian atrophy and Machado-Joseph disease: The mutant allele is preferentially transmitted in male meiosis 査読

    T Ikeuchi, S Igarashi, Y Takiyama, O Onodera, M Oyake, H Takano, R Koide, H Tanaka, S Tsuji

    AMERICAN JOURNAL OF HUMAN GENETICS58 ( 4 ) 730 - 733   1996年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:UNIV CHICAGO PRESS  

    Autosomal dominant dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph disease (MJD) are neurodegenerative disorders caused by CAG trinucleotide repeat expansions. An inverse correlation of age at onset with the length of the expanded CAG trinucleotide repeats has been demonstrated, and the intergenerational instability of the length of the CAG trinucleotide repeats, which is more prominent in paternal than in maternal transmissions, has been shown to underlie the basic mechanisms of anticipation in DRPLA and MJD. Our previous observations on DRPLA and MJD pedigrees, as well as a review of the literature, have suggested that the numbers of affected offspring exceed those of unaffected offspring, which is difficult to explain by the Mendelian principle of random segregation of alleles. In the present study, we analyzed the segregation patterns in 211 transmissions in 24 DRPLA pedigrees and 80 transmissions in 7 MJD pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (chi(2) = 7.69; P &lt; .01) and 73% in MJD (chi(2) = 6.82; P &lt; .01). The results were consistent with meiotic drive in DRPLA and MJD. Since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and meiotic drive is observed only in male meiosis, these results raise the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis.

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  • Lack of association between dopamine D2 receptor gene Cys311 variant and schizophrenia 査読

    T Tanaka, S Igarashi, O Onodera, H Tanaka, N Fukushima, M Takahashi, K Kameda, S Tsuji, S Ihda

    AMERICAN JOURNAL OF MEDICAL GENETICS67 ( 2 ) 208 - 211   1996年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Itokawa et al, [1993] reported identifying one missense nucleotide mutation from C to G resulting in a substitution of serine with cysteine at codon 311 in the third intracellular loop of the dopamine D2 receptor in schizophrenics, Arinami et al, [1994] reported finding a positive association between the Cys311 variant and schizophrenia. In response to the report by Arinami et al, [1994] we examined 106 unrelated Japanese schizophrenics and 106 normal controls to determine if there is any association of the Cys311 variant with schizophrenia. However, we found no statistically significant differences in allelic frequencies of Cys311 between schizophrenia and normal controls. The present results as well as those of all previous studies except for that of Arinami et al. [1994] indicated that an association between the dopamine D2 receptor gene and schizophrenia is unlikely to exist. (C) 1996 Wiley-Liss, Inc.

    DOI: 10.1002/(SICI)1096-8628(19960409)67:2<208::AID-AJMG12>3.0.CO;2-N

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  • Lack of association between dopamine D4 receptor gene and schizophrenia 査読

    T Tanaka, S Igarashi, O Onodera, H Tanaka, K Kameda, K Takahashi, S Tsuji, S Ihda

    AMERICAN JOURNAL OF MEDICAL GENETICS60 ( 6 ) 580 - 582   1995年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    An intriguing property of the dopamine D4 receptor gene is a hypervariable segment in the coding region characterized by a varying number of direct imperfect 48 bp repeats (2-8 or 10 repeats) in the third exon of he gene [Lichter et al., 1993: Hum Mol Genet 2:767-773]. The authors analyzed 70 unrelated schizophrenics and 70 normal controls to determine the allele and genotype frequencies created by length polymorphism of dopamine D4 receptor gene. All patients and controls were unrelated and from the Japanese population. Patients were divided into three groups with regard to age at onset, familial loading, and severity of symptoms assessed strictly with Manchester scale. There were no statistically significant differences if the distributions of alleles and genotypes were analyzed for schizophrenia as a whole or analyzed in consideration of those clinical subtypes, Lichter and colleagues [1993] have reported that at least 25 haplotypes exist for this polymorphic region of the. dopamine receptor D4 gene, In this study only the alleles created by length polymorphism were analyzed, and further investigation to determine the haplotypes of patients and controls on using a much larger sample size will be required. (C) 1995 Wiley-Liss, Inc.

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  • MOLECULAR-CLONING OF A FULL-LENGTH CDNA FOR DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY AND REGIONAL EXPRESSIONS OF THE EXPANDED ALLELES IN THE CNS 査読

    O ONODERA, M OYAKE, H TAKANO, T IKEUCHI, S IGARASHI, S TSUJI

    AMERICAN JOURNAL OF HUMAN GENETICS57 ( 5 ) 1050 - 1060   1995年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:UNIV CHICAGO PRESS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by genetic anticipation and variable combinations of symptoms including myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, and dementia. Recently, we discovered that DRPLA is caused by unstable expansion of a CAG repeat of a gene on the short arm of chromosome 12. We determined the consensus DRPLA cDNA sequence containing the complete coding region for 1,185 amino acids. The CAG repeat, which is expanded in DRPLA, is located 1,462 bp downstream from the putative methionine initiation codon and encodes a poly-glutamine tract. Although poly-serine and proline tracts exist near the CAG repeats, these polyserine or proline tracts did not show any polymorphisms, which is in strong contrast to the high heterogeneity in the length of the CAG repeat. Northern blot analysis revealed a 4.7-kb transcript that is widely expressed in various tissues including heart, lung, kidney, placenta, skeletal muscle, and brain. Reverse transcription-PCR analysis revealed that the expanded alleles are transcribed to levels comparable to those of normal alleles. These results indicate that there is no difference in transcriptional efficiency between expanded and normal alleles. Furthermore, mRNA from cerebellar hemispheres of DRPLA patients showed smaller sizes of CAG repeats compared with other regions of the brain, which reflects somatic mosaicism of the expanded alleles of the DRPLA gene.

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  • GENETIC ASSOCIATION OF THE VERY-LOW-DENSITY LIPOPROTEIN (VLDL) RECEPTOR GENE WITH SPORADIC ALZHEIMERS-DISEASE 査読

    K OKUIZUMI, O ONODERA, Y NAMBA, K IKEDA, T YAMAMOTO, K SEKI, A UEKI, S NANKO, H TANAKA, H TAKAHASHI, K OYANAGI, H MIZUSAWA, KANAZAWA, I, S TSUJI

    NATURE GENETICS11 ( 2 ) 207 - 209   1995年10月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING CO  

    DOI: 10.1038/ng1095-207

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY - CLINICAL-FEATURES ARE CLOSELY-RELATED TO UNSTABLE EXPANSIONS OF TRINUCLEOTIDE (CAG) REPEAT 査読

    T IKEUCHI, R KOIDE, H TANAKA, O ONODERA, S IGARASHI, H TAKAHASHI, R KONDO, A ISHIKAWA, A TOMODA, T MIIKE, K SATO, Y IHARA, T HAYABARA, F ISA, H TANABE, S TOKIGUCHI, M HAYASHI, N SHIMIZU, F IKUTA, H NAITO, S TSUJI

    ANNALS OF NEUROLOGY37 ( 6 ) 769 - 775   1995年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LITTLE BROWN CO  

    Dentatorubral-pallidoluysian atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of dentatorubral-pallidoluysian atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p &lt; 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of dentatorubral-pallidoluysian atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of dentatorubral-pallidoluysian atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.

    DOI: 10.1002/ana.410370610

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  • TRIAL TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION WITH ANTI-YO ANTIBODY .1. MOUSE STRAINS BEARING DIFFERENT MHC MOLECULES PRODUCE ANTIBODIES ON IMMUNIZATION WITH RECOMBINANT YO PROTEIN, BUT DO NOT CAUSE PURKINJE-CELL LOSS 査読

    M TANAKA, K TANAKA, O ONODERA, S TSUJI

    CLINICAL NEUROLOGY AND NEUROSURGERY97 ( 1 ) 95 - 100   1995年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:VAN GORCUM CO BV  

    Passive transfer of anti-Yo antibody from patients with paraneoplastic cerebellar degeneration (PCD) associated with gynecological or breast carcinoma has not been successful in inducing an animal model. We used active immunization with recombinant Yo protein of four strains of mice bearing different MHC molecules: BALB/c (H-2d), C3H (H-2k), C57BL/6 (H-2b), SJL/J (H-2s). All the strains produced high anti-Yo antibody titer but none developed cerebellar ataxia or showed Purkinje cell loss. Spleen cells from the immunized mice also reacted with recombinant protein. Because C57BL/6(nu/nu) mice produce no anti-Yo antibody, mature helper T cells are required for its production. Results suggest that antibody production in peripheral blood alone is not sufficient for the development of PCD and that MHC class II molecules function in the activation of T cells to help B cells produce antibodies.

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  • TRIAL TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION WITH ANTI-YO ANTIBODY .2. PASSIVE TRANSFER OF MURINE MONONUCLEAR-CELLS ACTIVATED WITH RECOMBINANT YO PROTEIN TO PARANEOPLASTIC CEREBELLAR DEGENERATION LYMPHOCYTES IN SEVERE COMBINED IMMUNODEFICIENCY MICE 査読

    K TANAKA, M TANAKA, S IGARASHI, O ONODERA, T MIYATAKE, S TSUJI

    CLINICAL NEUROLOGY AND NEUROSURGERY97 ( 1 ) 101 - 105   1995年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:VAN GORCUM CO BV  

    Passive transfer of serum IgG or mononuclear cells from peripheral blood of a patient with paraneoplastic cerebellar degeneration (PCD) to rodents was carried out in order to examine the role of anti-Purkinje cell antibody (anti-Yo antibody) present in serum and cerebrospinal fluid of PCD patients. After a single injection of IgG into mouse brain, it was taken up by Purkinje cells and remained there for more than 36 h without Purkinje cell loss. Injection of PCD IgG together with complement or lipopolysaccharide-activated human macrophages or rat mononuclear cells into rat ventricles did not cause Purkinje cell loss. We also studied passive transfer of the PCD patient's lymphocytes to mice with severe combined immunodeficiency (SCID). We constructed a recombinant Yo fusion protein that has the leucine-zipper protein (Yo protein), the common epitope for anti-Yo antibody for immunizing mice, and that resulted in production of significant amounts of anti-Yo antibody. Spleen cells from these Yo protein immunized mice were injected intravenously or intracerebrally into naive mice that subsequently showed no neurological symptoms or loss of Purkinje cells. We conclude that the anti-Yo antibody, either in combination with or without complement or activated mononuclear cells, cannot be the sole cause of Purkinje cell loss.

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - CLOSE CORRELATION OF CAG REPEAT EXPANSIONS WITH THE WIDE SPECTRUM OF CLINICAL PRESENTATIONS AND PROMINENT ANTICIPATION 査読

    T IKEUCHI, O ONODERA, M OYAKE, R KOIDE, H TANAKA, S TSUJI

    SEMINARS IN CELL BIOLOGY6 ( 1 ) 37 - 44   1995年2月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS (LONDON) LTD  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy and dementia as well as various ages of onset. We have identified a specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 as the pathogenic mutation for DRPLA. We investigated how the degree of the expansion of the CAG repeat affects the clinical manifestations of DRPLA. The sires of the expanded alleles were well correlated with the ages of onset (r = -0.6955, P&lt;0.001). Patients with progressive myoclonus epilepsy (PME) phenotype had larger expansions (62-79 repeats) and earlier ages of onset (onset before age 20). Furthermore, most of the patients with PME phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with non-PME phenotype showed later ages of onset (onset after age 20) and smaller expansions (54-67 repeats). When ages of onset of each clinical symptom are compared with sizes of the CAG repeat, there is again a remarkably high correlation of the sizes of CAG repeat with each of the clinical symptoms. Thus the wide variation in clinical manifestations of DRPLA can now be clearly explained based on-the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.

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  • LONG-TERM COURSE OF CHANGE IN ANTI-YO ANTIBODY CONTENT IN PARANEOPLASTIC CEREBELLAR DEGENERATION 査読

    K TANAKA, M TANAKA, S IGARASHI, O ONODERA, T NAKAJIMA, M YAMAZAKI, T MIYATAKE, S TSUJI

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY58 ( 2 ) 256 - 257   1995年2月

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    記述言語:英語   出版者・発行元:BRITISH MED JOURNAL PUBL GROUP  

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  • Auditory comprehension in transcortical motor aphasia due to a medial lesions of the left frontal lobe 査読

    M. Otsuki, Y. Soma, O. Onodera, S. Tsuji, A. Satoh, N. Yamada

    Brain and Nerve47 ( 11 ) 1081 - 1085   1995年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We assessed the anatomical findings and auditory comprehension of six patients with transcortical motor aphasia due to medial lesions of the left frontal lobe. All patients were right handed and were initially mute for several hours after the onset, and they exhibited mild paresis of the right lower extremity. Their spontaneous speech was sparse and not fluent, and sometimes accompanied by echolalia, but their articulation was normal and repetition was excellent. They had difficulty in recalling words. A diagnosis of transcortical motor aphasia was made on the basis of their clinical symptoms. All patients were found to have an infarct in the left medial frontal region by MRI and/or CT. We administered the Western Aphasia Battery and 50 line drawing pointing task in order to evaluate auditory comprehension. Based on the results we concluded that there is no impairment of auditory comprehension of single words when lesions are limited to the superior frontal gyrus, but that lesions extending to the middle frontal gyrus interfere with auditory comprehension of single words. Our observations indicate that the middle frontal gyrus plays an important role in auditory comprehension of single words. All of the patients displayed impaired auditory comprehension of sentences even when their lesions were strictly limited to the medial frontal lobe. This suggests that the medial frontal lobe plays some role in the auditory comprehension of sentences.

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  • Trial to establish an animal model of paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibody 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to naive SJL or PCD lympphocytes to severe combined immunodefic 査読

    Tanaka K, Tanaka M, Igarashi S, Onodera O, Miyatake T, Tsuji S

    Clin Neurol Neurosurg97   101 - 105   1995年

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  • Paraneoplastic cerebellar degeneration - Characterization of anti-yo antibody and underlying cancer 査読

    K. Tanaka, M. Tanaka, O. Onodera, S. Tsuji

    Clinical Neurology35 ( 7 ) 770 - 774   1995年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A group of patients with paraneoplastic cerebellar degeneration (PCD) have shown to produce auto-antibody to both neurons and tumor cells (anti-Yo antibody). More than 60% of these patients have shown neurological symptoms and anti-Yo antibody production before the underlying cancers were found, which suggests that the test for anti-Yo antibody is important for the early detection and treatment of cancer. Originally, anti-Yo antibody has been characterized as 1)labelling the cytoplasm of cerebellar Purkinje cells immunohistochemically, 2)binding to the 62 and 34kDa bands on immunoblots of Purkinje cell extracts, 3) being present in female patients with gynecological or breast cancers. Recently, the common binding-epitope of anti-Yo antibody has been reported as leucine-zipper protein. In order to detect the anti-Yo antibody precisely, we examined the immunohistochemical and western blot characters of the recombinant leucine-zipper protein- reactive (anti-Yo) antibody. The results were, 1)sera containing leucine- zipper protein-reactive antibody labels both cerebellar Purkinje cells but some sera might contain other antibodies together with anti-Yo that confuse the immunostaining character of anti-Yo antibody, 2)the antibody binds to 58 kDa band and sometimes co-binds to 34kDa on immunoblots of cerebellar tissue extracts. The underlying cancers are mainly adenocarcinoma in the ovary, fallopian tube, uterus, or breast but occasionally large cell lung and bile duct cancers have been found. Interestingly, a male patient had an antibody similar in character to be anti-Yo antibody immunohistochemically and on immunoblots, that did not recognize leucine-zipper protein and the underlying carcinoma was small cell lung cancer. These results suggest that 1) the diagnosis of anti-Yo antibody should be based on the antibody's reactivity with leucine-zipper protein, 2) some sera with the anti-Yo antibody label other tissues besides the Purkinje cell cytoplasm because of the co-existance of other antibodies seen immunohistochemically and on immunoblots, 3) the search for underlying cancers should not be limited to gynecological or breast carcinomas.

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  • Lack of association between dopamine D4 receptor gene and schizophrenia 査読

    T. Tanaka, S. Igarashi, O. Onodera, H. Tanaka, K. Kameda, K. Takahashi, S. Tsuji, S. Ihda

    American Journal of Medical Genetics - Neuropsychiatric Genetics60 ( 6 ) 580 - 582   1995年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An intriguing property of the dopamine D4 receptor gene is a hypervariable segment in the coding region characterized by a varying number of direct imperfect 48 bp repeats (2-8 or 10 repeats) in the third exon of the gene [Lichter et al., 1993: Hum Mol Genet 2:767-773]. The authors analyzed 70 unrelated schizophrenics and 70 normal controls to determine the allele and genotype frequencies created by length polymorphism of dopamine D4 receptor gene. All patients and controls were unrelated and from the Japanese population. Patients were divided into three groups with regard to age at onset, familial loading, and severity of symptoms assessed strictly with Manchester scale. There were no statistically significant differences if the distributions of alleles and genotypes were analyzed for schizophrenia as a whole or analyzed in consideration of those clinical subtypes. Lichter and colleagues [1993] have reported that at least 25 haplotypes exist for this polymorphic region of the dopamine receptor D4 gene. In this study only the alleles created by length polymorphism were analyzed, and further investigation to determine the haplotypes of patients and controls on using a much larger sample size will be required.

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  • PARTIAL DELETIONS OF PUTATIVE ADRENOLEUKODYSTROPHY (ALD) GENE IN JAPANESE ALD PATIENTS 査読

    R KOIKE, O ONODERA, H TABE, K KANEKO, T MIYATAKE, S IWASAKI, M NAKANO, N SHIZUMA, K IKEGUCHI, M NISHIZAWA, J MOSSER, CO SARDE, S TSUJI

    HUMAN MUTATION6 ( 3 ) 263 - 267   1995年

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    DOI: 10.1002/humu.1380060314

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  • DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) - MOLECULAR-BASIS FOR WIDE CLINICAL-FEATURES OF DRPLA 査読

    T IKEUCHI, R KOIDE, O ONODERA, H TANAKA, M OYAKE, H TAKANO, S TSUJI

    CLINICAL NEUROSCIENCE3 ( 1 ) 23 - 27   1995年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder characterized clinically by various combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, dementia and psychiatric symptoms. Based on the phenomenon of anticipation, the gene for DRPLA was recently identified. DRPLA is caused by unstable expansion of a CAG repeat in the gene located on the short arm of chromosome 12. As have been observed in Huntington's disease and SCA1, there is a strong correlation between the age of onset and the size of CAG repeats. Furthermore, patients with larger repeats tend to show a PME (progressive myoclonus epilepsy) phenotype as well as earlier ages of onset. More prominent anticipation and larger intergenerational increase of CAG repeats in paternal transmission can be accounted for by the meiotic instability of CAG repeats in male gametogenesis. Comparison of size distributions of CAG repeats in Japanese, African-American and white populations revealed that 7.4% of the Japanese alleles had greater than 19 repeats, whereas none of the whites and 1% of the African-American alleles were of this size. The results may account for the ethnic predilection of DRPLA. (C) 1995 Wiley-Liss, Inc.

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  • PASSIVE TRANSFER AND ACTIVE IMMUNIZATION WITH THE RECOMBINANT LEUCINE-ZIPPER (YO) PROTEIN AS AN ATTEMPT TO ESTABLISH AN ANIMAL-MODEL OF PARANEOPLASTIC CEREBELLAR DEGENERATION 査読

    K TANAKA, M TANAKA, O ONODERA, S IGARASHI, T MIYATAKE, S TSUJI

    JOURNAL OF THE NEUROLOGICAL SCIENCES127 ( 2 ) 153 - 158   1994年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Passive transfer of paraneoplastic cerebellar degeneration (PCD) IgG to rodents as well as active immunization with recombinant Yo fusion protein were tried in order to examine the roles of anti-Purkinje cell antibody (anti-Yo antibody) present in the sera and cerebrospinal fluid of patients with PCD in Purkinje cell loss, the hall mark of PCD pathology. On a single injection of PCD IgG to mouse brain, IgG was taken into Purkinje cells and remained there for more than 36 h without Purkinje cell loss. Injection of PCD IgG together with complement or lipopolysaccharide-activated human macrophages or rat mononuclear cells to rats ventricles did not cause Purkinje cell loss. We made a recombinant Yo fusion protein that has the leucine-zipper protein (Yo protein), the common epitope for anti-Yo antibody. Mice immunized with this Yo protein produced high titer antibody against it for more than 3 months, during which time neither neurological symptoms nor Purkinje cell loss occurred. The anti-Yo antibody, with or without complement or activated mononuclear cells, therefore could not be the sole cause of Purkinje cell loss.

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  • TRINUCLEOTIDE REPEAT LENGTH AND RATE OF PROGRESSION OF HUNTINGTONS-DISEASE 査読

    SN ILLARIOSHKIN, S IGARASHI, O ONODERA, ED MARKOVA, NN NIKOLSKAYA, H TANAKA, TZ CHABRASHWILI, NG INSAROVA, K ENDO, IA IVANOVASMOLENSKAYA, S TSUJI

    ANNALS OF NEUROLOGY36 ( 4 ) 630 - 635   1994年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LITTLE BROWN CO  

    The Huntington's disease gene contains an expanded unstable (CAG)(n) repeat, and the repeat lengths have been shown to correlate with the age of onset. Using detailed clinical scales, we evaluated the rate of progression of Huntington's disease and its relationship to the number of triplet repeats. We found significant positive correlation between the rate of progression of clinical symptoms (both neurological and psychiatric) and CAG repeat length. These data suggest an important role of expanded trinucleotide repeat length in affecting the pathological process during the entire course of Huntington's disease.

    DOI: 10.1002/ana.410360412

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  • APOE-EPSILON-4 AND EARLY-ONSET ALZHEIMERS 査読

    K OKUIZUMI, O ONODERA, H TANAKA, H KOBAYASHI, S TSUJI, H TAKAHASHI, K OYANAGI, K SEKI, M TANAKA, S NARUSE, T MIYATAKE, H MIZUSAWA, KANAZAWA, I

    NATURE GENETICS7 ( 1 ) 10 - 11   1994年5月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING CO  

    DOI: 10.1038/ng0594-10b

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  • UNSTABLE EXPANSION OF CAG REPEAT IN HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY (DRPLA) 査読

    R KOIDE, T IKEUCHI, O ONODERA, H TANAKA, S IGARASHI, K ENDO, H TAKAHASHI, R KONDO, A ISHIKAWA, T HAYASHI, M SAITO, A TOMODA, T MIIKE, H NAITO, F IKUTA, S TSUJI

    NATURE GENETICS6 ( 1 ) 9 - 13   1994年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING CO  

    Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

    DOI: 10.1038/ng0194-9

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  • The detection of anti-Purkinje cell antibody (anti-Yo antibody) by ELISA using recombinant Yo fusion protein 査読

    K. Tanaka, M. Tanaka, O. Onodera, S. Igarashi, S. Tsuji

    Brain and Nerve46 ( 1 ) 47 - 51   1994年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Paraneoplastic cerebellar degeneration (PCD) is a remote effect of cancer mediated by possibly immunological mechanisms. The sera and cerebrospinal fluid of PCD patients containing high titer autoantibody against cerebellar Purkinje cells had been reported. This antibody binds to 62-kD and 34-kD bands of cerebellar Purkinje cell homogenates (anti-Yo antibody). However, it is not always true that the autoantibody of this character on immunoblot and immunohistochemistry recognizes the same molecule. Recently, the DNA sequence encoding the Yo antigen, whose common epitope is a sequence containing leucine-zipper motif, was reported. We made the recombinant protein deduced from the cDNA clone encoding the leucine-zipper motif of the Yo antigen. Using this recombinant protein as the antigen for ELISA, the anti Yo antibodies in the sera and CSF were examined and 3 new patients with PCD possesing anti-Yo antibody were found. The sera of one patient, serially taken during several kinds of treatment were examined with this ELISA system, which revealed that the anti-Yo antibody titer was increased after plasmapheresis and reduced after tumor resection and anti-cancer chemotherapy. The early resection of malignant tumors may prevent the continuous production of high titer anti-Yo antibody and stop the progression of cerebellar tissue damage.

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  • Correlation between degrees of the CTG repeat expansion and clinical features of myotonic dystrophy 査読

    I. Eguchi, R. Koike, O. Onodera, K. Tanaka, H. Kondo, S. Tsuji

    Clinical Neurology34 ( 2 ) 118 - 123   1994年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The mutation in myotonic dystrophy gene has recently been identified as an unstable expanison of trinucleotide CTG repeat located at the 3'-untranslated region of myotoninprotein kinase gene. In this paper we report the correlation between the degree of CTG amplification and clinical features in 35 individuals with myotonic dystrophy. The analysis of CTG repeat expansion was performed with Southern blot hybridization. Genomic DNA from peripheral blood leukocytes was digested with a restriction endonuclease, Pst I, instead of commonly used EcoRI. Since small expansion (about 190 bp) could be detected with PstI digestion and furthermore, the DNA fragment did not contain insertion/deletion polymorphism, we were able to accurately determine the exact sizes of CTG repeat expansion. We have observed a tendency of earlier ages of onset with larger allele sizes. The good correlation between the size of the expansion and the severity in muscle weakness was clearly demonstrated especially if the analysis was focused on the patients at same age group at 40~45 years. The severity of motor disability was classified into three stages. The mean size of expansion was 0.33 ± 0.17 (M ± SD) kbp in stage I, 2.58 ± 1.42 kbp in stage II, and 4.75 ± 0.93 kbp in stage III. The tendency was also observed when patients were categorized according to the intellectual grade. The anticipation was observed in all the parent-child pairs. When the increases of the repeat expansions were compared between father-child and mother-child transmissions, broader variation of the increases was observed in father-child transmissions. Our study indicates that Southern blot hybridization analysis of leukocyte genomic DNA was effective for the evaluation of muscle weakness and mental deficiency based on the sizes of the expanded allele.

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  • MRI findings of posterior spinal artery syndrome - Report of a case 査読

    K. Okuizumi, M. Wakasugi, O. Onodera, H. Okumura, S. Tsuji

    Clinical Neurology34 ( 11 ) 1116 - 1120   1994年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 58-year-old woman presented with sudden onset of numbness and weakness of the lower limbs. She showed paraparesis associated with hyperreflexia and pathological reflexes in lower limbs. She showed decreased sensation of vibration and proprioception in lower limbs, as well as tingling sensation below Th11 level. Pinprick and thermal sensations were spared. Magnetic resonance imaging (MRI) of the spinal cord revealed a symmetric high signal intensity area at the posterior medial part of the spinal cord spanning Th9 to Th11 on T2-weighted and proton density images. On the basis of clinical findings as well as MRI findings, we made a diagnosis of posterior spinal artery syndrome. The MRI findings are considered to be highly useful for the diagnosis of PSAS.

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  • USE OF A RADIATION-REDUCED HYBRID PANEL FOR THE LOCALIZATION OF 7 MARKERS IN THE XQ28 REGION OF THE HUMAN GENOME 査読

    A SMAHI, B PETERLIN, O ONODERA, S TSUJI, MC FULCHIGNONILATAUD

    ANNALES DE GENETIQUE37 ( 1 ) 11 - 13   1994年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EXPANSION SCI FRANCAISE  

    Two genes (QM and biglycan), three cDNAs expressed in the brain (TH4, TH27, p877) and two microsatellites (AFM224zg11 and AFM287ze5) are assigned in the six sub regions delimited by an IRHs panel of the human Xq28 region.

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  • CHROMOSOMAL LOCALIZATION OF THE EPSILON-1, EPSILON-3, AND ZETA-1 SUBUNIT GENES OF THE HUMAN NMDA RECEPTOR-CHANNEL 査読

    H TAKANO, O ONODERA, H TANAKA, H MORI, K SAKIMURA, T HORI, H KOBAYASHI, M MISHINA, S TSUJI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS197 ( 2 ) 922 - 926   1993年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

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  • ABSENCE OF LINKAGE DISEQUILIBRIUM AT AMYLOID PRECURSOR PROTEIN GENE LOCUS IN JAPANESE FAMILIAL ALZHEIMERS-DISEASE WITH 717VAL-]ILE MUTATION 査読

    H TANAKA, S NARUSE, K SEKI, O ONODERA, H KOBAYASHI, T MIYATAKE, A SHIBATA, Y SAKAKI, K KAMINO, T MIKI, N NUKINA, M IMAGAWA, NAKANO, I, T SHIMIZU, T KOJIMA, J HARDY, S TSUJI

    NEUROSCIENCE LETTERS162 ( 1-2 ) 63 - 66   1993年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    To date, eleven independent FAD pedigrees with the 717Val--&gt;Ile mutation have been identified. Interestingly, five pedigrees were of Japanese origin and four were of British origin. The apparent ethnic prediction of this mutation raises the possibility that there is a founder effect in these two island nations. We did not observe any significant linkage disequilibrium in any locus of APP and GT12 loci in the five Japanese FAD pedigrees with the 717Val--&gt;Ile mutation. A founder effect would probably not be present in Japanese FAD pedgrees with the 717Val--&gt;Ile mutation.

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  • [Positional cloning--current status and future directions]. 査読

    Onodera O, Tsuji S

    Nihon rinsho. Japanese journal of clinical medicine51 ( 9 ) 2225 - 2233   1993年9月

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  • [Molecular genetic approach for positional cloning of X-chromosome-linked diseases]. 査読

    Onodera O, Tanabe H, Tuji S, Kaneko K, Kobayashi H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme38 ( 3 ) 354 - 360   1993年2月

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  • HTRA1 Disorder 査読

    Osamu Onodera, Hiroaki Nozaki, Toshio Fukutake

        1993年

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    記述言語:英語   出版者・発行元:University of Washington, Seattle  

    CLINICAL CHARACTERISTICS: HTRA1 disorder is a phenotypic spectrum in which some individuals have few to no symptoms and others manifest with the more severe CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) phenotype. Those who have a heterozygous HTRA1 pathogenic variant may have mild neurologic findings (sometimes identified only on neuroimaging) or mild-to-moderate neurologic signs and symptoms of CARASIL. In this chapter, the term "classic CARASIL" refers to the more severe phenotype associated with biallelic pathogenic variants, and "HTRA1 cerebral small vessel disease" (HTRA1-CSVD) refers to the milder phenotype associated with a heterozygous HTRA1 pathogenic variant. Classic CARASIL is characterized by early-onset changes in the deep white matter of the brain observed on MRI, and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 40 years. Forty-four percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly following the onset of neurologic symptoms. Scalp alopecia and acute mid- to lower-back pain (lumbago) before age 30 years are characteristic. The most frequent initial symptom in individuals with HTRA1-CSVD is slowly progressive gait disturbance after age 40 years, which may be followed by the development of mood changes and cognitive dysfunction. A majority of affected individuals have a stroke-like episode after age 40 years. Spondylosis and alopecia are seen in a minority of individuals with HTRA1-CSVD. DIAGNOSIS/TESTING: The diagnosis of HTRA1 disorder is established in a proband by identification of either a heterozygous or biallelic pathogenic variant(s) in HTRA1 on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Consideration of anti-platelet therapy and anti-hypertensive therapy for those with cerebral microbleeds; physical therapy, walking aids, and home adaptations for those with gait disturbance; consideration of medication (baclofen or tizanidine) for spasticity; wig or hairpiece for those with alopecia; standard treatment for spinal spondylosis and mood disorder; supportive care including emotional support and counseling for affected individuals and their families. Surveillance: Follow-up intervals are based on the severity and type of symptoms and the needs of the individuals and their caregivers. Agents/circumstances to avoid: Smoking and a high-salt diet, which may hasten the progression of arteriosclerosis. GENETIC COUNSELING: HTRA1 disorder caused by biallelic pathogenic variants (i.e., the classic CARASIL phenotype) is inherited in an autosomal recessive manner. HTRA1 disorder caused by heterozygous pathogenic variants is inherited in an autosomal dominant manner. Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of inheriting both HTRA1 pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither pathogenic variant and not being at risk for HTRA1 disorder. Autosomal dominant inheritance. Each sib of an affected individual has a 50% risk of inheriting the pathogenic variant from their affected parent. Once the HTRA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HTRA1 disorder are possible.

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  • CARASIL 査読

    Onodera O, Nozaki H, Fukutake T, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A

        1993年

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  • MRI findings of olivopontocerebellar atrophy and Machado-Joseph disease - Diagnostic value of transverse pontine fibers 査読

    J. Idezuka, O. Onodera, T. Yuasa, S. Tsuji, J. Ito

    Clinical Neurology33 ( 3 ) 289 - 293   1993年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Spinocerebellar Ataxia Type 17 査読

    Yasuko Toyoshima, Osamu Onodera, Mitsunori Yamada, Shoji Tsuji, Hitoshi Takahashi

        1993年

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    記述言語:英語   出版者・発行元:University of Washington, Seattle  

    CLINICAL CHARACTERISTICS: Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course. DIAGNOSIS/TESTING: The diagnosis of SCA17 is established in a proband by identification of an abnormal CAG/CAA repeat expansion in TBP. Affected individuals usually have more than 41 repeats. The CAA and CAG codons both encode glutamine residues resulting in a pathogenic polyglutamine expansion. MANAGEMENT: Treatment of manifestations: Psychotropic medications for psychiatric problems, antiepileptic drugs for seizures (AEDs); botulinum toxin injections for dystonia; adaptation of the environment to accommodate dementia. Prevention of secondary complications: Side effects of psychotropic medications and AEDs may require total or intermittent discontinuation of the treatment or reduction in dose. Surveillance: Annual or semiannual evaluation by a neurologist or more frequently if symptoms are progressing rapidly. Agents/circumstances to avoid: Sedative/hypnotic agents, such as ethanol or certain medications, may exacerbate incoordination. GENETIC COUNSELING: SCA17 is inherited in an autosomal dominant manner. Offspring of affected individuals are at a 50% risk of inheriting the expanded TBP allele. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion. Prenatal testing for pregnancies at increased risk is possible if the diagnosis has been established in an affected family member by molecular genetic testing.

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  • STRONG CORRELATION BETWEEN THE NUMBER OF CAG REPEATS IN ANDROGEN RECEPTOR GENES AND THE CLINICAL ONSET OF FEATURES OF SPINAL AND BULBAR MUSCULAR-ATROPHY 査読

    S IGARASHI, Y TANNO, O ONODERA, M YAMAZAKI, S SATO, A ISHIKAWA, N MIYATANI, M NAGASHIMA, Y ISHIKAWA, K SAHASHI, T IBI, T MIYATAKE, S TSUJI

    NEUROLOGY42 ( 12 ) 2300 - 2302   1992年12月

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    記述言語:英語   出版者・発行元:LIPPINCOTT-RAVEN PUBL  

    X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by androgen receptor gene mutations with an increased number of tandem CAG repeats in exon 1. We investigated the increased number of CAG repeats in androgen receptor genes of 19 SBMA patients and found that this correlated strongly with the age at onset of muscle weakness. Thus, SBMA is the first genetic disease in which a strong correlation between the degree of genetic abnormality (number of CAG tandem repeats) and clinical phenotypic expression is demonstrable. The results further indicate that androgen gene mutation is directly involved in the degeneration of motor neurons.

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  • GENOMIC ORGANIZATION OF A CDNA (QM) DEMONSTRATING AN ALTERED MESSENGER-RNA LEVEL IN NONTUMORIGENIC WILMS MICROCELL HYBRID-CELLS AND ITS LOCALIZATION TO XQ28 査読

    K KANEKO, H KOBAYASHI, O ONODERA, T MIYATAKE, S TSUJI

    HUMAN MOLECULAR GENETICS1 ( 7 ) 529 - 533   1992年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Using a cosmid clone derived from human Xq28 as a probe which shows cross-species homology, we isolated cDNA clones and the nucleotide sequence analysis of the cDNA revealed that the cDNA is identical to QM cDNA. The QM cDNA has recently been reported as a cDNA with down-regulation in tumorigenic Wilms&apos; tumor microcell hybrid. Comparison of the nucleotide sequences of the cDNA with those of the genomic DNA allowed us to determine the genomic organization of the QM gene. The QM gene consists of at least 7 exons and is located at Xq28. Southern blot analysis of a somatic cell hybrid panel indicates that the QM genes are scattered at least to chromosome 2, 3, 6, 14, 16, and possibly to other chromosomes. Northern blot analysis demonstrated the QM gene is expressed in ali the examined adult human tissues as well as cell lines including HeLa cells, fibroblasts, and somatic cell hybrids with increased expression in liver, spleen, testis, and adrenal gland. The results suggest that the QM gene belongs to a new multi-gene family with yet undetermined function.

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  • RAPID DIAGNOSIS OF TUBERCULOUS MENINGITIS BY POLYMERASE CHAIN-REACTION (PCR) 査読

    K KANEKO, O ONODERA, T MIYATAKE, S TSUJI

    NEUROLOGY40 ( 10 ) 1617 - 1618   1990年10月

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    記述言語:英語   出版者・発行元:LITTLE BROWN CO  

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  • ATRIAL STANDSTILL AFTER TREADMILL EXERCISE TEST AND UNIQUE RESPONSE TO ISOPROTERENOL INFUSION IN RECURRENT POSTEXERCISE SYNCOPE 査読

    Y TAMURA, O ONODERA, K KODERA, Y IGARASHI, T MIIDA, Y AIZAWA, T IZUMI, A SHIBATA, S TAKANO

    AMERICAN JOURNAL OF CARDIOLOGY65 ( 7 ) 533 - 535   1990年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EXCERPTA MEDICA INC  

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  • A case of rigid spine syndrome with rimmed vacuole 査読

    O. Onodera, M. Yamazaki, T. Atsumi, T. Miyatake, T. Izumi

    Clinical Neurology30 ( 5 ) 516 - 519   1990年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • [Research into actual conditions and preventive care in periodontal disease. Relationship between questionnaire results and periodontal disease in youth]. 査読

    Nakashima K, Kurihara C, Kawanaga T, Kurihashi Y, Ohsawa K, Onodera O, Shimoyama M, Watanabe Y, Ikeda K

    Nihon Shishubyo Gakkai kaishi31 ( 4 ) 1220 - 1241   1989年12月

  • [A method of protection on out-flow of hydroxyapatite]. 査読

    Watanabe Y, Kurihara N, Nakashima K, Onodera O, Ousawa K, Mashima T, Kurihashi Y, Miyata T, Ikeda K

    Nihon Shishubyo Gakkai kaishi30 ( 4 ) 1108 - 1115   1988年12月

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  • [The study of dentifrice containing Phellodendron amurense extract on periodontal disease (II). The clinical effects of dentifrice containing Phellodendron amurense extract and anti-inflammatory agents]. 査読

    Sato I, Watanabe Y, Shimojima T, Onodera O, Ohsawa K, Nakajima K, Kurihashi Y, Mashima T, Kusunoki K, Ikeda K

    Nihon Shishubyo Gakkai kaishi30 ( 3 ) 887 - 900   1988年9月

  • [Preventive and epidemic research in periodontal disease. 1. Study of preventive and epidemic research in periodontal disease in psychopathic patients]. 査読

    Ikeda K, Kusunoki K, Osawa K, Kurihashi Y, Onodera O, Kin H, Iwakawa Y, Nishimoto M

    Nihon Shishubyo Gakkai kaishi28 ( 2 ) 654 - 661   1986年6月

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  • [Systemic considerations in the improvement of periodontal disease]. 査読

    Kusunoki K, Shimojima T, Onodera O, Ohsawa K, Miyake T

    Josai Shika Daigaku kiyo. The Bulletin of the Josai Dental University13 ( 3 ) 592 - 602   1984年

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  • [Study of orthodontic problems in patients with periodontal disease. 2. The malposition of teeth in periodontal disease]. 査読

    Kusunoki K, Shimojima T, Onodera O, Yamamoto O, Iwakawa Y, Ikeda K

    Josai Shika Daigaku kiyo. The Bulletin of the Josai Dental University13 ( 1 ) 83 - 92   1984年

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  • [Clinical evaluation of regional myocardial blood flow in patients with hypertrophic cardiomyopathy]. 査読

    Sekiguchi H, Fukuhara Y, Koh M, Narita H, Yamanaka T, Fujino Y, Mikuniya A, Onodera O

    Journal of cardiography13 ( 4 ) 1059   1983年12月

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▶ 全件表示

書籍等出版物

  • 厚生労働科学研究費補助金難治性疾患克服研究事業遺伝性脳小血管病の病態機序の解明と治療法の開発班研究報告書

    小野寺, 理

    [小野寺理]  2010年3月 

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    総ページ数:37p   記述言語:日本語

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  • 転写障害に注目した神経変性過程の解明

    小野寺, 理

    [小野寺理]  2005年3月 

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    総ページ数:112p  

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  • アプラタキシン欠損症の臨床遺伝学的検討および病態機序の解明

    辻, 省次, 後藤, 順, 小野寺, 理, 小宅, 睦郎

    辻省次  2004年3月 

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    総ページ数:22p   記述言語:英語

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MISC

  • ANCA関連脊髄肥厚性硬膜炎の臨床免疫病理学的検討

    中島 章博, 佐治 越爾, 清水 宏, 豊島 靖子, 岡本 浩一郎, 若杉 尚宏, 柳村 文寛, 柳川 香織, 柿田 明美, 小野寺 理, 河内 泉

    神経免疫学25 ( 1 ) 134 - 134   2020年10月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • 認知症と精神疾患の鑑別における血液バイオマーカーの有用性の検討

    樋口 陽, 春日 健作, 徳武 孝允, 宮下 哲典, 茂木 崇治, 横山 裕一, 福井 直樹, 染矢 俊幸, 小野寺 理, 池内 健

    Dementia Japan34 ( 4 ) 527 - 527   2020年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • Intracortical and corticospinal spreading of TDP-43 in mouse FTLD/ALS models(和訳中)

    坪口 晋太朗, 中村 由香, 石原 智彦, 加藤 泰介, 小山 哲秀, 佐藤 時春, 吉田 富, 上野 将紀, 小野寺 理

    Dementia Japan34 ( 4 ) 524 - 524   2020年10月

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    記述言語:英語   出版者・発行元:(一社)日本認知症学会  

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  • 多発性硬化症における大脳萎縮の解析

    若杉 尚宏, 佐治 越爾, 中島 章博, 柳村 文寛, 柳川 香織, 小野寺 理, 河内 泉

    神経免疫学25 ( 1 ) 106 - 106   2020年10月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • 進行性腎細胞癌へのニボルマブ・イピリムマブ併用療法後に生じた自己免疫性脳炎の1例

    小林 彩夏, 小出 眞悟, 佐治 越爾, 山名 一寿, 河内 泉, 富田 善彦, 小野寺 理

    神経免疫学25 ( 1 ) 131 - 131   2020年10月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • 重症筋無力症合併視神経脊髄炎関連疾患の解析

    佐治 越爾, 中島 章博, 若杉 尚宏, 柳川 香織, 小野寺 理, 河内 泉

    神経免疫学25 ( 1 ) 115 - 115   2020年10月

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    記述言語:日本語   出版者・発行元:日本神経免疫学会  

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  • 著明な疼痛と異常感覚で発症した筋萎縮性側索硬化症の1例

    池上 いちこ, 畠山 公大, 羽入 龍太郎, 滑川 将気, 大津 裕, 金澤 雅人, 小野寺 理

    臨床神経生理学48 ( 5 ) 587 - 587   2020年10月

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    記述言語:日本語   出版者・発行元:(一社)日本臨床神経生理学会  

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  • ゲノム編集による遺伝子サイレンシングを用いたDRPLA治療戦略

    安藤 昭一朗, 加藤 泰介, 小池 佑佳, 廣川 祥子, 小林 憲太, 辻 省次, 小野寺 理

    Dementia Japan34 ( 4 ) 531 - 531   2020年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • 【良性成人型家族性ミオクローヌスてんかん】良性成人型家族性ミオクローヌスてんかんの神経病理

    齊ノ内 信, Ramil Gabdulkhaev, 小野寺 理, 柿田 明美

    脳神経内科93 ( 3 ) 305 - 309   2020年9月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • 肺血栓塞栓症を合併し、奇異性塞栓による後脊髄動脈症候群を呈した潰瘍性大腸炎の56歳女性例

    荻根沢 真也, 上村 昌寛, 大津 裕, 徳武 孝允, 金澤 雅人, 小野寺 理

    臨床神経学60 ( 5 ) 367 - 367   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Elevated serum pentraxin 3 levels might predict the diagnosis of branch atheromatous disease at a very early stage. 国際誌

    Itaru Ninomiya, Masato Kanazawa, Masahiro Umemura, Osamu Onodera

    European journal of neurology   2020年4月

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    記述言語:英語  

    BACKGROUND: Branch atheromatous disease (BAD) is one of the stroke subtypes caused by occlusion at the origin of a deep penetrating artery of the brain and is associated with a microatheroma or a junctional plaque. Patients with BAD often develop progressive worsening of neurologic deficits, although these patients often present minor stroke with clinical characteristics of lacunar syndrome at the onset. Pentraxin 3 (PTX3) is known to be a key molecule involved in the pathogenesis of atherosclerosis. Although a high level of serum PTX3 is observed in patients with acute coronary syndrome, there are no reports on PTX3 levels in patients with BAD. This study aimed to investigate whether serum PTX3 levels can distinguish BAD from other stroke subtypes. METHODS: We investigated 93 patients with ischemic stroke. Serum PTX3 levels on admission were measured using enzyme-linked immunosorbent assay in patients with BAD and those of other stroke subtypes (each n ≥ 20). RESULTS: The median PTX3 levels in patients with BAD (4840 pg/mL) were higher than those with other subtypes of stroke (3397 pg/mL in lacunar stroke, 1298 pg/mL in large artery atherosclerosis, 1470 pg/mL in cardioaortic embolism, and 1006 pg/mL in control) (all p < 0.01). CONCLUSION: Our results suggest that elevated serum pentraxin 3 levels might predict the diagnosis of BAD at a very early stage.

    DOI: 10.1111/ene.14249

    PubMed

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  • 【まれな感染症-ウイルス,細菌,寄生虫,輸入感染症-】脳神経領域のまれな感染症 画像診断のポイント

    岡本 浩一郎, 高橋 陽彦, 鈴木 倫明, 小野寺 理, 柿田 明美, 阿部 博史

    臨床放射線65 ( 4 ) 317 - 324   2020年4月

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    記述言語:日本語   出版者・発行元:金原出版(株)  

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  • サルコペニア・フレイルの視点からの認知症

    小野寺 理

    Therapeutic Research41 ( 2 ) 91 - 94   2020年2月

  • 抗GD1aIgM抗体と抗GT1bIgM抗体が陽性で免疫グロブリン療法が奏功した遠位優位型CIDPの76歳男性例

    羽入 龍太郎, 須貝 章弘, 加藤 怜, 秋山 夏葵, 徳武 孝允, 金澤 雅人, 河内 泉, 小野寺 理

    臨床神経学60 ( 1 ) 87 - 87   2020年1月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Huntington病の診断、治療、療養の手引き

    中島 健二, 祖父江 元, 長谷川 一子, 饗場 郁子, 青木 正志, 阿部 康二, 池内 健, 小野寺 理, 梶 龍兒, 吉良 潤一, 桑原 聡, 小久保 康昌, 斎藤 加代子, 佐々木 秀直, 佐野 輝, 高橋 良輔, 辻 省次, 戸田 達史, 中川 正法, 野元 正弘, 服部 信孝, 村田 美穂, 村山 繁雄, 望月 秀樹, 森田 光哉, 横田 隆徳, 吉田 眞理, 渡辺 保裕, 保住 功, Huntington病の診断、治療、療養の手引きガイドライン作成委員会

    神経治療学37 ( 1 ) 61 - 104   2020年1月

  • 【ジストニア診療のupdate】ジストニア 遺伝子診断からのアプローチ

    加藤 怜, 石原 智彦, 小野寺 理

    脳神経内科91 ( 6 ) 727 - 738   2019年12月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • 外科的介入を受けていない症候性もやもや病の1剖検例

    齋藤 祥二, 齋藤 理恵, 中原 亜紗, 長谷川 仁, 田口 貴博, 上村 昌寛,