2024/04/23 更新

写真a

コヤマ アキヒデ
小山 哲秀
KOYAMA Akihide
所属
教育研究院 医歯学系 医学系列 助教
医歯学総合研究科 地域疾病制御医学専攻 地域予防医学 助教
職名
助教
通称等の別名
koyamaa
外部リンク

学位

  • 博士(医学) ( 2017年3月   新潟大学 )

研究キーワード

  • 神経疾患

  • 法医学

  • 安定同位体

  • バイオマーカー

  • 透明化

  • 核酸検出

  • 核酸断片化

研究分野

  • ライフサイエンス / 法医学

  • ライフサイエンス / 神経内科学

  • ライフサイエンス / 基盤脳科学

経歴(researchmap)

  • 新潟大学   Graduate School of Medical and Dental Sciences   助教

    2017年7月 - 現在

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  • 新潟大学   Faculty of Medicine   助教

    2017年4月 - 現在

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  • 新潟大学   Brain Research Institute   特任助教

    2016年10月 - 2017年3月

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  • 新潟大学研究機構超域学術院 助教

    2012年4月 - 2016年9月

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経歴

  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻 地域予防医学   助教

    2017年4月 - 現在

  • 新潟大学   脳研究所   特任助教

    2016年10月 - 2017年3月

  • 新潟大学   研究推進機構 超域学術院   助教

    2011年4月 - 2016年9月

学歴

  • 新潟大学   Graduate School of Medical and Dental Sciences

    2017年3月

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  • 新潟大学   Graduate School of Medical and Dental Sciences   Master Course's Graduate Program for Biomedical Sciences

    2007年4月 - 2009年3月

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所属学協会

 

論文

  • Ultrasensitive malaria detection system for Anopheles mosquito field surveillance using droplet digital PCR. 国際誌

    Tamasa Araki, Akihide Koyama, Hiro Yoshimura, Ayako Arai, Satoru Kawai, Shuto Sekizawa, Yuko Umeki, Yumiko Saito-Nakano, Takashi Imai, Munehiro Okamoto, Megumi Sato, Wipaporn Thabthimthong, Taratorn Kemthong, Hajime Hisaeda, Suchinda Malaivijitnond, Takeshi Annoura

    Parasitology international   102891 - 102891   2024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)  

    Malaria remains a significant global public health concern, with a recent increase in the number of zoonotic malaria cases in Southeast Asian countries. However, limited reports on the vector for zoonotic malaria exist owing to difficulties in detecting parasite DNA in Anopheles mosquito vectors. Herein, we demonstrate for the first time that several Anopheles mosquitoes contain simian malaria parasite DNA using droplet digital PCR (ddPCR), a highly sensitive PCR method. An entomological survey was conducted to identify simian malaria vector species at Phra Phothisat Temple (PPT), central Thailand, recognized for a high prevalence of simian malaria in wild cynomolgus macaques. A total of 152 mosquitoes from six anopheline species were collected and first analyzed by a standard 18S rRNA nested-PCR analysis for malaria parasite which yielded negative results in all collected mosquitoes. Later, ddPCR was used and could detect simian malaria parasite DNA, i.e. Plasmodium cynomolgi, in 25 collected mosquitoes. And this is the first report of simian malaria parasite DNA detection in Anopheles sawadwongporni. This finding proves that ddPCR is a powerful tool for detecting simian malarial parasite DNA in Anopheles mosquitoes and can expand our understanding of the zoonotic potential of malaria transmission between monkeys and humans.

    DOI: 10.1016/j.parint.2024.102891

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  • Corrigendum: Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke. 国際誌

    Ninomiya I, Koyama A, Otsu Y, Onodera O, Kanazawa M

    Frontiers in cellular neuroscience   18   1372045 - 1372045   2024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)  

    [This corrects the article DOI: 10.3389/fncel.2023.1225504.].

    DOI: 10.3389/fncel.2024.1372045

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  • Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis. 国際誌

    Haruhiko Takahashi, Manabu Natsumeda, Norikazu Hara, Akihide Koyama, Hiroshi Shimizu, Akinori Miyashita, Daiken Satake, Yoshihiro Mouri, Jun Tsukano, Keita Kawabe, Yoshihiro Tsukamoto, Masayasu Okada, Ryosuke Ogura, Akihiko Yuki, Hajime Umezu, Akiyoshi Kakita, Takeshi Ikeuchi, Makoto Oishi

    Acta neuropathologica communications   12 ( 1 )   14 - 14   2024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)  

    Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

    DOI: 10.1186/s40478-024-01723-0

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  • Reliable detection of genetic alterations in cyst fluid DNA for the diagnosis of brain tumors. 国際誌

    Jotaro On, Manabu Natsumeda, Haruhiko Takahashi, Akihide Koyama, Satoshi Shibuma, Nao Shibata, Jun Watanabe, Shoji Saito, Yu Kanemaru, Yoshihiro Tsukamoto, Masayasu Okada, Ryosuke Ogura, Takeyoshi Eda, Mari Tada, Hiroshi Shimizu, Jun-Ichi Adachi, Kazuhiko Mishima, Ryo Nishikawa, Akiyoshi Kakita, Makoto Oishi

    Journal of neuro-oncology   166 ( 2 )   273 - 282   2024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)  

    PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

    DOI: 10.1007/s11060-023-04555-5

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  • Postmortem Identification of Genetic Variations Associated with Sudden Unexpected Death in Young People.

    Miura A, Yamamoto T, Funayama K, Koyama A, Takatsuka H, Sato T, Nishio H

    International heart journal   65 ( 1 )   55 - 62   2024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)  

    Sudden unexpected death in the young (SUDY) is a traumatic occurrence for their family; however, information on the genetic variations associated with the condition is currently lacking. It is important to carry out postmortem genetic analyses in cases of sudden death to provide information for relatives and to allow appropriate genetic counselling and clinical follow-up. This study aimed to investigate the genetic variations associated with the occurrence of SUDY in Japan, using next-generation sequencing (NGS). The study included 18 cases of SUDY (16 males, 2 females; age 15-47 years) who underwent autopsy, including NGS DNA sequencing for molecular analysis. A total of 168 genes were selected from the sequencing panel and filtered, resulting in the identification of 60 variants in cardiac disease-related genes. Many of the cases had several of these genetic variants and some cases had a cardiac phenotype. The identification of genetic variants using NGS provides important information regarding the pathogenicity of sudden death.

    DOI: 10.1536/ihj.23-252

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  • TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models. 査読 国際誌

    Shintaro Tsuboguchi, Yuka Nakamura, Tomohiko Ishihara, Taisuke Kato, Tokiharu Sato, Akihide Koyama, Hideki Mori, Yuka Koike, Osamu Onodera, Masaki Ueno

    Acta neuropathologica   146 ( 4 )   611 - 629   2023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)  

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

    DOI: 10.1007/s00401-023-02615-8

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  • Bleeding-Source Exploration in Subdural Hematoma: Observational Study on the Usefulness of Postmortem Computed Tomography Angiography. 査読 国際誌

    Kazuhisa Funayama, Akihide Koyama, Rieka Katsuragi-Go, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Diagnostics (Basel, Switzerland)   13 ( 13 )   2023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)  

    In a few cases, postmortem computed tomography angiography (PMCTA) is effective in postmortem detection of cortical artery rupture causing subdural hematoma (SDH), which is difficult to detect at autopsy. Here, we explore the usefulness and limitations of PMCTA in detecting the sites of cortical arterial rupture for SDH. In 6 of 10 cases, extravascular leakage of contrast material at nine different places enabled PMCTA to identify cortical arterial rupture. PMCTA did not induce destructive arterial artifacts, which often occur during autopsy. We found that, although not in all cases, PMCTA could show the site of cortical arterial rupture causing subdural hematoma in some cases. This technique is beneficial for cases of SDH autopsy, as it can be performed nondestructively and before destructive artifacts from the autopsy occur.

    DOI: 10.3390/diagnostics13132286

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  • Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease. 査読 国際誌

    Hideaki Matsui, Shinji Ito, Hideki Matsui, Junko Ito, Ramil Gabdulkhaev, Mika Hirose, Tomoyuki Yamanaka, Akihide Koyama, Taisuke Kato, Maiko Tanaka, Norihito Uemura, Noriko Matsui, Sachiko Hirokawa, Maki Yoshihama, Aki Shimozawa, Shin-Ichiro Kubo, Kenji Iwasaki, Masato Hasegawa, Ryosuke Takahashi, Keisuke Hirai, Akiyoshi Kakita, Osamu Onodera

    Proceedings of the National Academy of Sciences of the United States of America   120 ( 23 )   e2214652120   2023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)  

    α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.

    DOI: 10.1073/pnas.2214652120

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  • Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke. 査読 国際誌

    Itaru Ninomiya, Akihide Koyama, Yutaka Otsu, Osamu Onodera, Masato Kanazawa

    Frontiers in cellular neuroscience   17   1225504 - 1225504   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Theoretically, direct chemical reprogramming of somatic cells into neurons in the infarct area represents a promising regenerative therapy for ischemic stroke. Previous studies have reported that human fibroblasts and astrocytes transdifferentiate into neuronal cells in the presence of small molecules without introducing ectopic transgenes. However, the optimal combination of small molecules for the transdifferentiation of macrophages into neurons has not yet been determined. The authors hypothesized that a combination of small molecules could induce the transdifferentiation of monocyte-derived macrophages into neurons and that the administration of this combination may be a regenerative therapy for ischemic stroke because monocytes and macrophages are directly involved in the ischemic area. Transcriptomes and morphologies of the cells were compared before and after stimulation using RNA sequencing and immunofluorescence staining. Microscopic analyses were also performed to identify cell markers and evaluate functional recovery by blinded examination following the administration of small molecules after ischemic stroke in CB-17 mice. In this study, an essential combination of six small molecules [CHIR99021, Dorsomorphin, Forskolin, isoxazole-9 (ISX-9), Y27632, and DB2313] that transdifferentiated monocyte-derived macrophages into neurons in vitro was identified. Moreover, administration of six small molecules after cerebral ischemia in model animals generated a new neuronal layer in the infarct cortex by converting macrophages into neuronal cells, ultimately improving neurological function. These results suggest that altering the transdifferentiation of monocyte-derived macrophages by the small molecules to adjust their adaptive response will facilitate the development of regenerative therapies for ischemic stroke.

    DOI: 10.3389/fncel.2023.1225504

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  • Detection and Morphological Analysis of Micro-Ruptured Cortical Arteries in Subdural Hematoma: Three-Dimensional Visualization Using the Tissue-Clearing Clear, Unobstructed, Brain/Body Imaging Cocktails and Computational Analysis Method. 査読 国際誌

    Kazuhisa Funayama, Kazuki Tainaka, Akihide Koyama, Rieka Katsuragi-Go, Natsumi Nishikawa-Harada, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Diagnostics (Basel, Switzerland)   12 ( 11 )   2022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)  

    One of the causes of bleeding in subdural hematoma is cortical artery rupture, which is difficult to detect at autopsy. Therefore, reports of autopsy cases with this condition are limited and hence, the pathogenesis of subdural hematoma remains unclear. Herein, for the detection and morphological analysis of cortical artery ruptures as the bleeding sources of subdural hematoma, we used the tissue-clearing CUBIC (clear, unobstructed, brain/body imaging cocktails and computational analysis) method with light-sheet fluorescence microscopy and reconstructed the two-dimensional and three-dimensional images. Using the CUBIC method, we could clearly visualize and detect cortical artery ruptures that were missed by conventional methods. Indeed, the CUBIC method enables three-dimensional morphological analysis of cortical arteries including the ruptured area, and the creation of cross-sectional two-dimensional images in any direction, which are similar to histopathological images. This highlights the effectiveness of the CUBIC method for subdural hematoma analysis.

    DOI: 10.3390/diagnostics12112875

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  • FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA inC9orf72-linked ALS/FTD 査読 国際誌

    Yuzo Fujino, Morio Ueyama, Taro Ishiguro, Daisaku Ozawa, Toshihiko Sugiki, Hayato Ito, Asako Murata, Akira Ishiguro, Tania F. Gendron, Kohji Mori, Eiichi Tokuda, Tomoya Taminato, Takuya Konno, Akihide Koyama, Yuya Kawabe, Toshihide Takeuchi, Yoshiaki Furukawa, Toshimichi Fujiwara, Manabu Ikeda, Toshiki Mizuno, Hideki Mochizuki, Hidehiro Mizusawa, Keiji Wada, Kinya Ishikawa, Osamu Onodera, Kazuhiko Nakatani, Hideki Taguchi, Leonard Petrucelli, Yoshitaka Nagai

    eLife   12   2022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)  

    Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

    DOI: 10.1101/2022.11.01.514717

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  • Endogenous human retrovirus-K is not increased in the affected tissues of Japanese ALS patients. 査読 国際誌

    Tomohiko Ishihara, Akihide Koyama, Yuya Hatano, Ryoko Takeuchi, Yuka Koike, Taisuke Kato, Mari Tada, Akiyoshi Kakita, Osamu Onodera

    Neuroscience research   178   78 - 82   2022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)  

    Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

    DOI: 10.1016/j.neures.2022.01.009

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  • PROS1 variant in sudden death case of pulmonary embolism caused by calcification in the inferior vena cava: The importance of postmortem genetic analysis. 査読 国際誌

    Aya Miura, Kazuhisa Funayama, Hiromi Nyuzuki, Naoya Takahashi, Takuma Yamamoto, Akihide Koyama, Takeshi Ikeuchi, Hisakazu Takatsuka, Hajime Nishio

    Legal medicine (Tokyo, Japan)   55   102029 - 102029   2022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)  

    A Japanese man in his 30s died suddenly. Postmortem computed tomography and autopsy revealed a pulmonary embolism from an organizing thrombus in the inferior vena cava as the cause of death. Genomic analysis of congenital thrombophilia-related genes (i.e., SERPINC1, PROC, PROS1, F2, F5, PLG, and MTHFR) revealed a heterozygous variant of PROS1 (p.A139V), which has been reported in patients with congenital protein S deficiency. After a genetic conference that included forensic pathologists, molecular scientists, genetic researchers, genetic clinicians, and clinical physicians, the results of the genetic analysis were explained to the family. Biochemical analyses of protein S (PS) activity and total PS antigen levels were performed with samples from the deceased's family and genetic analysis was not performed until clinical symptoms appear. Herein we demonstrate the importance of genetic background in cases of a sudden death due to pulmonary embolism.

    DOI: 10.1016/j.legalmed.2022.102029

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  • Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model. 査読 国際誌

    Taisuke Kato, Ri-Ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

    The Journal of clinical investigation   131 ( 22 )   2021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)  

    Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

    DOI: 10.1172/JCI140555

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  • The usefulness of postmortem computed tomography angiography for subdural hematoma caused by rupture of the cortical artery: A report of two autopsy cases and a literature review. 査読 国際誌

    Kazuhisa Funayama, Kazuki Harada, Akihide Koyama, Rieka Katsuragi-Go, Natsumi Nishikawa-Harada, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Naoya Takahashi, Hisakazu Takatsuka

    Legal medicine (Tokyo, Japan)   53   101941 - 101941   2021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)  

    Acute subdural hematoma (SDH) occurs following severe head trauma with brain contusion or rupture of bridging veins. Conversely, SDH caused by rupture of a cortical artery without trauma or with minor trauma is also possible. Although over 150 cases of the latter SDH have been reported, they were predominantly diagnosed only during surgery, and therefore, no adequate histological evaluation has been performed. Therefore, essential etiology of this SDH type has remained unclear. In addition, the scarcity of autopsy cases may be attributed to arterial rupture being missed if the macroscopic findings are too minimal to detect during autopsy. Here, we describe two autopsy cases of SDH of cortical artery origin. Extravasation on postmortem computed tomography angiography and arterial leakage on macroscopic observation during autopsy facilitated detection of the ruptured artery and allowed detailed histological evaluation of the ruptured artery and adjacent dura mater. The etiology of arterial rupture is briefly described on the basis of histopathological findings in this study and the available literature.

    DOI: 10.1016/j.legalmed.2021.101941

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  • Corrigendum: 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 neurology   12   756038 - 756038   2021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:FRONTIERS MEDIA SA  

    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.2021.756038

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  • FTLD/ALSモデルマウスにおけるTDP-43の皮質内と皮質脊髄内での増殖(Intracortical and corticospinal spreading of TDP-43 in mouse FTLD/ALS models)

    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 Japan   34 ( 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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  • 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 Japan   34 ( 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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  • HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature 査読

    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 NEUROLOGY   11   2020年7月

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    記述言語:英語   出版者・発行元:FRONTIERS MEDIA SA  

    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 inhigh-temperature requirement A serine peptidase 1(HTRA1). Recently, it was reported that several heterozygous mutations inHTRA1also cause cerebral small vessel disease (CSVD). Although patients with heterozygousHTRA1-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 onHTRA1-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, heterozygousHTRA1-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 withHTRA1-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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  • 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. Genetics   6 ( 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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  • Hemorrhagic cerebral small vessel disease caused by a novel mutation in 3 ' UTR of collagen type IV alpha 1 査読

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

    NEUROLOGY-GENETICS   6 ( 1 )   2020年2月

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

    DOI: 10.1212/NXG.0000000000000383

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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 neurology   11   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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  • 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 disease   130   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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  • Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation 査読

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

    NEUROBIOLOGY OF DISEASE   130   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)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    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 TDP43 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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  • HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade.

    Masahiro Uemura, Nozaki H, Koyama A, Sakai N, Ando S, Masato Kanazawa, Taisuke Kato, Osamu Onodera

    Frontiers in neurology   2019年6月

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    掲載種別:研究論文(学術雑誌)  

    <b>Background:</b> Mutations in the <i>high-temperature requirement A serine peptidase 1 (HTRA1)</i> cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for <i>HTRA1</i> 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. <b>Methods:</b> 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. <b>Results:</b> 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 (<i>P</i> = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (<i>P</i> = 0.162). <b>Conclusions:</b> 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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  • 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 NEUROLOGY   10   756038 - 756038   2019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:FRONTIERS MEDIA SA  

    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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  • An autopsy case of peliosis hepatis with X-linked myotubular myopathy. 査読 国際誌

    Kazuhisa Funayama, Hiroshi Shimizu, Hidetomo Tanaka, Izumi Kawachi, Ichizo Nishino, Kou Matsui, Naoya Takahashi, Akihide Koyama, Rieka Katsuragi-Go, Ryoko Higuchi, Takashi Aoyama, Hiraku Watanabe, Akiyoshi Kakita, Hisakazu Takatsuka

    Legal medicine (Tokyo, Japan)   38   77 - 82   2019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)  

    This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis.

    DOI: 10.1016/j.legalmed.2019.04.005

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  • ショウジョウバエモデルによるC9-ALS/FTDの病態解明

    上山 盛夫, 石黒 太郎, Gendron Tania F, 今野 卓哉, 小山 哲秀, 望月 秀樹, 和田 圭司, 石川 欣也, 小野寺 理, 永井 義隆

    Dementia Japan   32 ( 3 )   435 - 435   2018年9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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  • 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

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

    FRONTIERS IN NEUROSCIENCE   12   2018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:FRONTIERS MEDIA SA  

    Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasmand 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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  • 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 neuroscience   12   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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  • 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 SCIENCES   381   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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  • Distinct Molecular Mechanisms of Htra1 Mutants in Manifesting Heterozygotes With Carasil

    Hiroaki Nozaki, Taisuke Kato, Megumi Nihonmatsu, Yohei Saito, Ikuko Mizuta, Tomoko Noda, Ryoko Koike, Kazuhide Miyazaki, Muichi Kaito, Shoichi Ito, Masahiro Makino, Akihide Koyama

    STROKE   48   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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  • Toxicity of dipeptide repeat proteins in C9 ALS/FTD model fly

    Morio Ueyama, Taro Ishiguro, Tania F. Gendron, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Kinya Ishikawa, Keiji Wada, Leonard Petrucelli, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   91 ( 6 )   365 - 365   2016年12月

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    記述言語:英語   出版者・発行元:GENETICS SOC JAPAN  

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

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

    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology   84   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.

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

    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 research   44 ( 12 )   5820 - 36   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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  • 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

    Neurology   86 ( 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 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

    NEUROLOGY   86 ( 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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  • Establishment of a novel animal model of ALS/FTD expressing G4C2 repeat RNA in Drosophila

    Morio Ueyama, Taro Ishiguro, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Keiji Wada, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   90 ( 6 )   366 - 366   2015年12月

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    記述言語:英語   出版者・発行元:GENETICS SOC JAPAN  

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  • ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA. 査読 国際誌

    Yajima R, Tokutake T, Koyama A, Kasuga K, Tezuka T, Nishizawa M, Ikeuchi T

    Biochemical and biophysical research communications   456 ( 1 )   482 - 8   2015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)  

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  • Emerging molecular mechanism for cerebral small vessel disease: Lessons from hereditary small vessel disease

    Osamu Onodera, Yumi Sekine, Taisuke Kato, Akihide Koyama, Hiroaki Nozaki, Masatoyo Nishizawa

    NEUROLOGY AND CLINICAL NEUROSCIENCE   3 ( 1 )   7 - 13   2015年1月

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    記述言語:英語   出版者・発行元:WILEY  

    Cerebral small vessel disease is a common disorder in the elderly. The findings of hereditary small vessel disease studies clearly show that small vessel diseases have a distinct molecular pathway that is different from that in large vessels. However, the anatomical and functional heterogeneity of the cerebral small vessel system makes it difficult to understand the concept and molecular mechanism for small vessel disease. The purpose of this review is to explain the heterogeneity of small vessels and the importance of the components of the capillary system in the pathogenesis of cerebral small vessel disease. Although traditional investigations have focused more attention on the arteriole, the most functional part of small arteries is the capillary. Therefore, the capillary might play an important role in the pathogenesis of small vessel disease. In the capillary, pericytes and astrocytes are unique components with marked diversity. However, the molecular signature and function of pericytes remain unknown. Furthermore, the morphology and molecular signature of astrocytes in the cortex and white matter are quite different. Therefore, the mechanism of small vessel disease is not simple, and must be investigated considering the diversities of small vessels. In the capillary, cross-talk between cell components exists. Among these cell signaling pathways, recent findings on the gene responsible for hereditary small vessel disease show that transforming growth factor-beta and platelet-derived growth factor-beta could contribute to the molecular pathogenesis of small vessel disease. These findings provide useful information for the development of a new therapeutic strategy for small vessel disease.

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  • ApoE-isoform-dependent cellular uptake of amyloid-beta is mediated by lipoprotein receptor LR11/SorLA

    Ryuji Yajima, Takayoshi Tokutake, Akihide Koyama, Kensaku Kasuga, Toshiyuki Tezuka, Masatoyo Nishizawa, Takeshi Ikeuchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   456 ( 1 )   482 - 488   2015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:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The formation of senile plaques composed of beta-amyloid (A beta) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE epsilon 4 allele, the strong genetic factor for AD, facilitates the A beta deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-beta (A beta) through the binding of A beta to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of A beta through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4 > apoE3 > apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled A beta were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular A beta into the recipient cells was most prominently accentuated when co-cultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of A beta mediated by LR11/SorLA. (C) 2014 Elsevier Inc. All rights reserved.

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  • Establishment of a novel animal model of AILS expressing GGGGCC repeat RNA in Drosophila

    Morio Ueyama, Taro Ishiguro, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Keiji Wada, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   89 ( 6 )   334 - 334   2014年12月

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    記述言語:英語   出版者・発行元:GENETICS SOC JAPAN  

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

    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

    Neurology   82 ( 2 )   139 - 48   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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  • Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. 査読 国際誌

    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 genetics   22 ( 20 )   4136 - 47   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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  • 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

    NEUROLOGY   80   2013年2月

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  • What is the key player in TDP-43 pathology in ALS: Disappearance from the nucleus or inclusion formation in the cytoplasm?

    Osamu Onodera, Akihiro Sugai, Takuya Konno, Mari Tada, Akihide Koyama, Masatoyo Nishizawa

    NEUROLOGY AND CLINICAL NEUROSCIENCE   1 ( 1 )   11 - 17   2013年1月

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    記述言語:英語   出版者・発行元:WILEY  

    C9ORF72 and the 43 kDa TAR DNA-binding protein (TDP-43) are key molecules in the development of TDP-43 pathology in amyotrophic lateral sclerosis (ALS). The hexanucleotide repeat expansion in C9ORF72 also leads to frontotemporal lobar degeneration, whereas mutation of TARDBP mainly causes ALS, indicating that TDP-43 plays a more fundamental role in the development of ALS. In tissues affected with ALS, TDP-43 is dislocated from the nucleus, forms cytoplasmic inclusions, and is phosphorylated and truncated. Accumulating evidence suggests that the disappearance of TDP-43 from the nucleus precedes inclusion formation, indicating that its disappearance from the nucleus is crucial in the development of TDP-43 pathology. Alterations in the quality and quantity of TDP-43 might result in the disappearance of TDP-43 from the nucleus. Regarding quality, phosphorylation and truncation of TDP-43 is not necessary for its disappearance from the nucleus or for inclusion formation. Although it has been speculated that studies of TDP-43 harboring ALS-associated mutations are useful for understanding the molecular pathogenesis of sporadic ALS, the functional and biochemical differences between mutated and wild-type TDP-43 remain unclear. Regarding quantity, an increased amount of TDP-43 is an attractive hypothesis as it has been shown that increased amounts of TDP-43 are toxic. Moreover, several reports have suggested that increased levels of TDP-43 are found in sporadic ALS as well as in ALS with TDP-43 mutations. However, these findings remain controversial. Increased understanding of the mechanisms responsible for regulating TDP-43 will provide a basis for determining the molecular pathogenesis of ALS.

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

    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

    Hum Mol Genet.   20 ( 9 )   1800 - 10   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)  

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

    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

    Brain : a journal of neurology   134 ( Pt 5 )   1387 - 99   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 ∼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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  • Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia

    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

    BRAIN   134   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.

    DOI: 10.1093/brain/awr069

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  • Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-beta 1 via cleavage of proTGF-beta 1

    Atsushi Shiga, Hiroaki Nozaki, Akio Yokoseki, Megumi Nihonmatsu, Hirotoshi Kawata, Taisuke Kato, Akihide Koyama, Kunimasa Arima, Mari Ikeda, Shinichi Katada, Yasuko Toyoshima, Hitoshi Takahashi, Akira Tanaka, Imaharu Nakano, Takeshi Ikeuchi, Masatoyo Nishizawa, Osamu Onodera

    HUMAN MOLECULAR GENETICS   20 ( 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)   出版者・発行元:OXFORD UNIV PRESS  

    Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-beta (TGF-beta) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-beta family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-beta 1 signaling triggered by proTGF-beta 1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-beta 1 in the endoplasmic reticulum (ER), and cleaved proTGF-beta 1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-beta 1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-proTGF-beta 1, specifically, the intracellular cleavage of proTGF-beta 1 in the ER.

    DOI: 10.1093/hmg/ddr063

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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

    NEUROLOGY   74 ( 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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  • Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. 査読 国際誌

    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

    The New England journal of medicine   360 ( 17 )   1729 - 39   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, nonhypertensive, 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-beta1 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.

    DOI: 10.1056/NEJMoa0801560

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis. 査読 国際誌

    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

    Annals of neurology   63 ( 4 )   538 - 42   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-LISS  

    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.

    DOI: 10.1002/ana.21392

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  • TDP-43 mutation in familial amyotrophic lateral sclerosis

    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 NEUROLOGY   63 ( 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.

    DOI: 10.1002/ana.21392

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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 RESEARCH   61   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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  • TDP-43 mutation in familial amyotrophic lateral sclerosis

    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 RESEARCH   61   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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  • Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3 '-phosphate and 3 '-phosphoglycolate ends

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

    NUCLEIC ACIDS RESEARCH   35 ( 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.

    DOI: 10.1093/nar/gkm158

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  • Aprataxin, the causative gene product for AOA1/EAOH, repairs damaged 3'-ends of DNA single strand breaks

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

    NEUROLOGY   68 ( 12 )   A79 - A79   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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  • Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends. 査読 国際誌

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

    Nucleic acids research   35 ( 11 )   3797 - 809   2007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: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.

    DOI: 10.1093/nar/gkm158

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MISC

  • TDP-43 differentially propagates to induce degeneration in the motor circuit

    坪口晋太朗, 中村由香, 石原智彦, 加藤泰介, 佐藤時春, 小山哲秀, 森秀樹, 小池佑佳, 小野寺理, 小野寺理, 上野将紀

    Dementia Japan   37 ( 4 )   2023年

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  • マウスモデルにおける直接皮質脊髄路接続を介するTDP-43の拡散

    TSUBOGUCHI Shintaro, NAKAMURA Yuka, ISHIHARA Tomohiko, KATO Taisuke, KOYAMA Akihide, SATO Tokiharu, YOSHIDA Yutaka, UENO Masaki, ONODERA Osamu

    日本神経学会学術大会プログラム・抄録集   61st   2020年

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  • C9-ALS/FTDモデルショウジョウバエにおけるリピート関連非ATG翻訳の制御

    上山 盛夫, 石黒 太郎, Gendron Tania F, 今野 卓哉, 小山 哲秀, 和田 圭司, 石川 欣也, 小野寺 理, Petrucelli Leonard, 永井 義隆

    Dementia Japan   33 ( 4 )   551 - 551   2019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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  • IDH変異型グリオーマの診断と術中治療―コラボレーションを通して実現を目指す―

    棗田学, 阿部英明, 岡田正康, 五十嵐博中, 中田力, 小山哲秀, 小野寺理, 柿田明美, 大石誠, 藤井幸彦

    日本蛋白質科学会年会プログラム・要旨集   18th   25   2018年5月

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  • 家族性脳小血管病患者で報告された変異型HTRA1蛋白質の機能解析

    上村 昌寛, 野崎 洋明, 加藤 泰介, 小山 哲秀, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1P - 1241]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • 家族性脳小血管病患者で報告された変異型HTRA1蛋白質の機能解析

    上村 昌寛, 野崎 洋明, 加藤 泰介, 小山 哲秀, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1P - 1241]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • ALS原因遺伝子TDP-43の点変異によるアレル特異的遺伝子発現の変化

    須貝 章弘, 廣川 祥子, 小山 哲秀, 今野 卓哉, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [3P - 1118]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • RVCL関連変異の細胞内局在についての検討

    笠原 杏子, 加藤 泰介, 野崎 洋明, 小山 哲秀, 小野寺 理

    Dementia Japan   31 ( 4 )   572 - 572   2017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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  • SMN遺伝子欠失は日本における下位運動ニューロン疾患の発症リスクと関連する(SMN gene deletion is associated with developing risk of lower motor neuron disease in Japan)

    豊田 佐織, 石原 智彦, 小山 哲秀, 西澤 正豊, 小野寺 理

    臨床神経学   56 ( Suppl. )   S230 - S230   2016年12月

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    記述言語:英語   出版者・発行元:(一社)日本神経学会  

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  • Toxicity of dipeptide repeat proteins in C9 ALS/FTD model fly

    Morio Ueyama, Taro Ishiguro, Tania F. Gendron, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Kinya Ishikawa, Keiji Wada, Leonard Petrucelli, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   91 ( 6 )   365 - 365   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:GENETICS SOC JAPAN  

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  • C9ALS/FTDモデルショウジョウバエにおけるジペプチドリピートタンパク質の毒性

    上山盛夫, 上山盛夫, 石黒太郎, 石黒太郎, 石黒太郎, TANIA Gendron, 藤掛伸宏, 今野卓哉, 小山哲秀, 小野寺理, 石川欣也, 和田圭司, LEONARD Petrucelli, 永井義隆, 永井義隆

    日本遺伝学会大会プログラム・予稿集   88th   2016年

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  • Establishment of a novel animal model of ALS/FTD expressing G4C2 repeat RNA in Drosophila

    Morio Ueyama, Taro Ishiguro, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Keiji Wada, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   90 ( 6 )   366 - 366   2015年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:GENETICS SOC JAPAN  

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  • 異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 ALSではいつ細胞障害が始まるのか?TDP-43陽性封入体との関係

    小野寺理, 須貝章弘, 小山哲秀, 加藤泰介, 志賀篤, 今野卓哉, 小山美咲, 石原智彦, 西澤正豊

    異常タンパク伝播仮説に基づく神経疾患の画期的治療法の開発 平成26年度 総括・分担研究報告書   2015年

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  • G4C2リピートRNAを発現する新規ALS/FTDモデルショウジョウバエの樹立

    上山盛夫, 石黒太郎, 石黒太郎, 藤掛伸宏, 今野卓哉, 小山哲秀, 小野寺理, 和田圭司, 永井義隆

    日本遺伝学会大会プログラム・予稿集   87th   2015年

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  • HDLSはCSF-1Rの機能喪失で生じる シグナル伝達障害とハプロ不全

    勇 亜衣子, 今野 卓哉, 他田 正義, 他田 真理, 小山 哲秀, 野崎 洋明, 金田 大太, 田代 裕一, 山本 徹, 高橋 均, 西澤 正豊, 小野寺 理, 柿田 明美, 池内 健

    臨床神経学   54 ( Suppl. )   S8 - S8   2014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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  • Establishment of a novel animal model of AILS expressing GGGGCC repeat RNA in Drosophila

    Morio Ueyama, Taro Ishiguro, Nobuhiro Fujikake, Takuya Konno, Akihide Koyama, Osamu Onodera, Keiji Wada, Yoshitaka Nagai

    GENES & GENETIC SYSTEMS   89 ( 6 )   334 - 334   2014年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:GENETICS SOC JAPAN  

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  • ALS関連TARDBP遺伝子変異は自身の選択的スプライシングに影響をおよぼすか?

    今野 卓哉, 小山 哲秀, 逸見 文昭, 小山 美咲, 須貝 章弘, 加藤 泰介, 石原 智彦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S200 - S200   2014年12月

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  • γセクレターゼによるインスリン受容体の膜内切断および細胞内局在の検討

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  • Aprataxin, the causative gene product for AOA1/EAOH, repairs damaged 3'-ends of DNA single strand breaks

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  • aprataxinはDNA修復において校正機能を担うのか?

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  • 脊髄小脳変性症はapratoxinというタンパク質をつくるが,これは3'-5'エキソヌクレアーゼである(Spinocerebellar degeneration caused protein, aprataxin, is a 3'-5' exonuclease)

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共同研究・競争的資金等の研究

  • コロナ禍及び災害時における迅速臨時検査室の確立

    研究課題/領域番号:22K17302

    2022年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:若手研究

    提供機関:日本学術振興会

    小山 哲秀

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

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  • ヒト毛髪と水道水安定同位体組成に基づいた地理的居住領域予測モデルの開発

    研究課題/領域番号:19K19484

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:若手研究

    提供機関:日本学術振興会

    小山 哲秀

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    ヒト毛髪と水道水安定同位体組成に基づくヒトの地理的居住領域を予測するツールの開発を目的に研究を行なった。DNA型解析などの“個人を識別する”技術革新は進歩している一方で、候補者の絞り込みを行う方法の提唱は、本邦では未だなされていない。本研究では、この絞り込みの方法として、毛髪と水道水中の酸素と水素安定同位体に着目して研究を行なった。その結果、極めて解像度の高い水道水同位体マップの作成することが出来た。この成果は、居住場所を推定するために極めて重要な資料となりうる。さらに、毛髪あるいは骨の安定同位体比の検証結果より、身元の推定に安定同位体比を利用することが有用である可能性が示唆された。

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  • 脳小血管の動的機能に注目した脳血管性認知症克服への戦略

    研究課題/領域番号:16H02656

    2016年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(A)

    提供機関:日本学術振興会

    小野寺 理, 豊島 靖子, 加藤 泰介, 小山 哲秀, 野崎 洋明

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    配分額:46670000円 ( 直接経費:35900000円 、 間接経費:10770000円 )

    認知症の克服は喫緊の課題であり、脳血管性認知症は主因の一つである。この病変として、脳の小血管が注目され脳小血管病と称される。この病態として、近年、神経活動依存性血流調節機構の障害が唱えられている。しかし、その分子病態は不明である。我々は遺伝性脳小血管病の原因遺伝子HTRA1を単離し、本症が組織増殖因子シグナルの亢進によることを明らかとした。さらに、非遺伝性の脳小血管病類似の平滑筋・周皮細胞の変性を伴うマウスにて脳小血管病の分子病態、特に、組織増殖因子シグナルによる小血管障害機構を明らかとした。

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  • 脳小血管病の解明と治療方法の確立:CARASILの病態機序からのアプローチ

    研究課題/領域番号:25293200

    2013年4月 - 2016年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    小野寺 理, 佐藤 俊哉, 豊島 靖子, 小山 哲秀

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    配分額:18720000円 ( 直接経費:14400000円 、 間接経費:4320000円 )

    近年,脳の小血管を主体とする疾患が脳小血管病として注目を集めている,本症は高齢者に高頻度で認められ,血管性認知症,さらに変性疾患にも寄与すると考えられてきている.私たちは,人で遺伝性に,脳の小血管を侵す疾病CARASILの病態機序を明らかにし本症ではHTRA1の酵素活性が低下し,TGF-βファミリーシグナルの亢進により引き起こされることを示してきた.本研究ではHTRA1の遺伝子欠損マウスの小血管にて壁細胞の変性と内膜の肥厚を示し,その生化学的特徴を明らかとした.

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担当経験のある授業科目

  • 医学論文を読む(ジャーナルクラブ)A

    2022年
    -
    現在
    機関名:新潟大学

  • 医療と法

    2022年
    -
    現在
    機関名:新潟大学

  • 特殊講義(法医学I)

    2022年
    -
    現在
    機関名:新潟大学

  • 法医学

    2020年
    -
    現在
    機関名:新潟大学

  • 医療と法

    2020年
    機関名:新潟大学