研究者詳細 - 小野寺　理

論文 - 小野寺　理

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TDP-43は運動回路の変性を誘導するために異なって伝播する(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, 上野将紀

Dementia Japan 37 ( 4 ) 680 - 680 2023年10月

The Multifaceted Regulation of TDP-43 Condensates at the Intersection of Physiology and Pathology: Implications for Neurodegenerative Diseases

Akihiro Sugai, Takuma Yamagishi, Shingo Koide, Osamu Onodera

Phase Separation in Living Cells 253 - 270 2023年9月

発作性の神経症状を繰り返し、多発する微小出血像を認めた硬膜移植歴を有する39歳男性例

畠山祐樹, 坪口晋太朗, 石黒敬信, 佐治越爾, 畠山公大, 島田斉, 金澤雅人, 小野寺理

臨床神経学 63 ( 9 ) 603 - 603 2023年9月

SCA6の浸透性に関する研究(Study of penetrance of SCA6)

Hatano Yuya, Ishihara Tomohiko, Hirokawa Sachiko, Onodera Osamu

臨床神経学 63 ( Suppl. ) S335 - S335 2023年9月

脳梗塞発症前のメトホルミン内服による脳小血管病に対する神経保護効果

秋山夏葵, 二宮格, 山城貴之, 上村昌寛, 服部頼都, 猪原匡史, 小野寺理, 金澤雅人

臨床神経学 63 ( Suppl. ) S310 - S310 2023年9月

発作性の神経症状を繰り返し、多発する微小出血像を認めた硬膜移植歴を有する39歳男性例

畠山祐樹, 坪口晋太朗, 石黒敬信, 佐治越爾, 畠山公大, 島田斉, 金澤雅人, 小野寺理

臨床神経学 63 ( 9 ) 603 - 603 2023年9月

新潟県,脊髄小脳変性疫学調査-臨床調査個人票による調査

小出眞悟, 本郷祥子, 秋山夏葵, 中村航世, 小野寺理

臨床神経学 63 ( Suppl. ) S297 - S297 2023年9月

【神経変性疾患の眼球運動異常】脊髄小脳変性症の眼球運動の特徴や異常

小出眞悟, 石原智彦, 小野寺理

神経眼科 40 ( 3 ) 222 - 228 2023年9月

記述言語：日本語出版者・発行元：日本神経眼科学会

脊髄小脳変性症(spinocerebellar degeneration:SCD)は主に小脳と脳幹が侵される神経変性疾患である.SCDは遺伝性と孤発性に分類され,多くの疾患を含み,それぞれ臨床的特徴も異なる.SCDで障害される小脳,脳幹は眼球運動の各要素,衝動性眼球運動,滑動性追従眼球運動,前庭眼反射,視運動性眼運動,輻湊,固視に関わる部位である.このため,SCDでは眼球運動障害の頻度が高く,しばしば疾患ごとに特徴的な眼球運動障害も認められる.神経眼科的評価としてこれらの特徴を理解する事は,SCDの診断に重要である.(著者抄録)

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【いま新薬で加速する神経変性疾患研究異常タンパク質の構造、凝集のしくみから根本治療の真の標的に迫る】(第1章)タンパク質構造と病態 ALS病態のカギを握る液-液相分離

小出眞悟, 須貝章弘, 小野寺理

実験医学 41 ( 12 ) 1883 - 1889 2023年8月

記述言語：日本語出版者・発行元：(株)羊土社

筋萎縮性側索硬化症(ALS)は運動ニューロンの喪失を特徴とする神経変性疾患である.ALSの運動ニューロン細胞質で認める凝集体の構成成分としてTDP-43やFUS,C9orf72遺伝子変異によるジペプチドリピート(DPR)などのタンパク質があり,これらは液-液相分離(LLPS)とよばれる物理現象とかかわっている.LLPSは膜のないオルガネラの形成など生理的な機能を担う一方で,その破綻は凝集体の形成に関与している.本稿ではALS病態に関連したLLPSの生理的な役割と,凝集体が引き起こす病態について概説し,今後の研究の展望を述べる.(著者抄録)

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FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD. 国際誌

Yuzo Fujino, Morio Ueyama, Taro Ishiguro, Daisaku Ozawa, Hayato Ito, Toshihiko Sugiki, Asako Murata, Akira Ishiguro, Tania 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, Leonard Petrucelli, Hideki Taguchi, Yoshitaka Nagai

eLife 12 2023年7月

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： 10.7554/eLife.84338

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Inappropriate interpretation of non-pathogenic HTRA1 variant as pathogenic. 国際誌

Masahiro Uemura, Sho Kitahara, Taisuke Kato, Hiroaki Nozaki, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

Annals of clinical and translational neurology 10 ( 7 ) 1261 - 1262 2023年7月

The clinical application of optimized AT(N) classification in Alzheimer’s clinical syndrome (ACS) and non-ACS conditions

Kensaku Kasuga, Tamao Tsukie, Masataka Kikuchi, Takayoshi Tokutake, Kazuo Washiyama, Soichiro Shimizu, Hiroshi Yoshizawa, Yasuko Kuroha, Ryuji Yajima, Hiroshi Mori, Yasuaki Arakawa, Kiyoshi Onda, Akinori Miyashita, Osamu Onodera, Takeshi Iwatsubo, Takeshi Ikeuchi

Neurobiology of Aging 127 23 - 32 2023年7月

Vegetable and Fruit Intake Frequency and Mortality in Patients With and Without Chronic Kidney Disease: A Hospital-Based Cohort Study. 国際誌

Minako Wakasugi, Akio Yokoseki, Masakazu Wada, Takeshi Momotsu, Kenji Sato, Hiroyuki Kawashima, Kazutoshi Nakamura, Osamu Onodera, Ichiei Narita

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 33 ( 4 ) 566 - 574 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Patients with advanced chronic kidney disease (CKD) are generally discouraged from consuming high amounts of vegetables and fruits given the potential risk of hyperkalemia. In the general population, however, lower vegetable and fruit intake is associated with higher mortality. This Japanese hospital-based prospective cohort study including non-CKD and CKD participants examined whether the frequency of vegetable and fruit intake is associated with mortality, and whether the presence of CKD modifies this association. METHODS: Participants were 2,006 patients who visited the outpatient department of a general hospital between June 2008 and December 2016 (55% men; mean age, 69 years). Among these participants, 902 (45%) and 131 (7%) were non-dialysis-dependent patients with CKD and hemodialysis patients, respectively. The frequency of vegetable and fruit intake was determined by a self-report questionnaire using an ordinal scale, "never or rarely," "sometimes," and "every day." Multivariable Cox proportional hazards analysis was conducted, adjusting for potential confounders. RESULTS: Vegetable and fruit intake frequency decreased with worsening CKD stage (P for trend < .001). Baseline serum potassium levels stratified by CKD stage were similar across the three vegetable and fruit intake frequency groups. During a median follow-up of 5.7 years, 561 participants died (47.1/1,000 person-years). Adjusted hazard ratios relative to the "every day" group were 1.25 (95% confidence interval, 1.04-1.52) and 1.60 (95% confidence interval, 1.23-2.08) for the "sometimes" and "never or rarely" groups, respectively, after adjusting for demographic factors, comorbidities, and CKD status. When stratified by CKD status, a similar, albeit non-significant, dose-dependent relationship was observed between vegetable and fruit intake frequency and all-cause mortality irrespective of CKD status, with no effect modification by CKD status (Pinteraction = .69). CONCLUSION: A lower frequency of vegetable and fruit intake is significantly associated with a higher risk of death regardless of CKD status.

DOI： 10.1053/j.jrn.2023.01.011

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[Disseminated herpes zoster complicated by lumbosacral polyradiculoneuritis and fibular neuropathy: A case report].

Kosei Nakamura, Shintaro Tsuboguchi, Itaru Ninomiya, Osamu Ansai, Masato Kanazawa, Osamu Onodera

Rinsho shinkeigaku = Clinical neurology 63 ( 6 ) 359 - 362 2023年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 74-year-old woman who presented with a skin eruption involving the left lateral leg along the L5 dermatome and widespread eruptions on the buttocks and trunk was diagnosed with disseminated herpes zoster (HZ). She also had left lower extremity muscle weakness. The pattern of distribution of muscle weakness and gadolinium-enhanced magnetic resonance imaging findings indicated polyradiculoneuritis mainly affecting the L5 spinal root. Moreover, we observed severe weakness of the left tibialis anterior muscle. Weakness of the other L5 myotomes reduced after antiviral treatment; however, left tibialis anterior muscle weakness persisted. We concluded that lumbosacral polyradiculoneuritis was attributable to varicella-zoster virus (VZV) infection, which also caused fibular neuropathy in this case. Retrograde transport of the VZV may have infected the fibular nerve throughout the sites of skin eruption. It is important to be mindful of simultaneous nerve root and peripheral nerve involvement in cases of motor paralysis associated with HZ infection.

DOI： 10.5692/clinicalneurol.cn-001848

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Progressive conus medullaris lesions are suggestive of intravascular large B-cell lymphoma. 国際誌

Sho Kitahara, Masato Kanazawa, Manabu Natsumeda, Aki Sato, Masanori Ishikawa, Kenju Hara, Hiroyuki Tabe, Kunihiko Makino, Kouichirou Okamoto, Nobuya Fujita, Akiyoshi Kakita, Yukihiko Fuji, Osamu Onodera

European journal of neurology 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

DOI： 10.1111/ene.15941

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Oxygen–Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke

Yutaka Otsu, Masahiro Hatakeyama, Takeshi Kanayama, Natsuki Akiyama, Itaru Ninomiya, Kaoru Omae, Taisuke Kato, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata, Masato Kanazawa

Neurotherapeutics 2023年6月

Preclinical Characterization of the Tau PET Tracer [<sup>18</sup>F]SNFT-1: Comparison of Tau PET Tracers 査読

Ryuichi Harada, Pradith Lerdsirisuk, Yuki Shimizu, Yuka Yokoyama, Yiqing Du, Kaede Kudo, Michinori Ezura, Yoichi Ishikawa, Ren Iwata, Miho Shidahara, Aiko Ishiki, Akio Kikuchi, Yuya Hatano, Tomohiko Ishihara, Osamu Onodera, Yasushi Iwasaki, Mari Yoshida, Yasuyuki Taki, Hiroyuki Arai, Yukitsuka Kudo, Kazuhiko Yanai, Shozo Furumoto, Nobuyuki Okamura

Journal of Nuclear Medicine jnumed.123.265593 - jnumed.123.265593 2023年6月

Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying NOTCH2NLC Repeat Expansion. 国際誌

Yusran Ady Fitrah, Yo Higuchi, Norikazu Hara, Takayoshi Tokutake, Masato Kanazawa, Kazuhiro Sanpei, Tomone Taneda, Akihiko Nakajima, Shin Koide, Shintaro Tsuboguchi, Midori Watanabe, Junki Fukumoto, Shoichiro Ando, Tomoe Sato, Yohei Iwafuchi, Aki Sato, Hideki Hayashi, Takanobu Ishiguro, Hayato Takeda, Toshiaki Takahashi, Nobuyoshi Fukuhara, Kensaku Kasuga, Akinori Miyashita, Osamu Onodera, Takeshi Ikeuchi

Brain sciences 13 ( 6 ) 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

DOI： 10.3390/brainsci13060955

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Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution. 国際誌

Priya Jagota, Yoshikazu Ugawa, Zakiyah Aldaajani, Norlinah Mohamed Ibrahim, Hiroyuki Ishiura, Yoshiko Nomura, Shoji Tsuji, Cid Diesta, Nobutaka Hattori, Osamu Onodera, Saeed Bohlega, Amir S N AlDin, Shen-Yang Lim, Jee-Young Lee, Beomseok Jeon, Pramod Kumar Pal, Huifang Shang, Shinsuke Fujioka, Prashanth Lingappa Kukkle, Onanong Phokaewvarangkul, Chin-Hsien Lin, Cholpon Shambetova, Roongroj Bhidayasiri

Journal of movement disorders 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

DOI： 10.14802/jmd.23065

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Accuracy of a machine learning method based on structural and locational information from AlphaFold2 for predicting the pathogenicity of TARDBP and FUS gene variants in ALS

Yuya Hatano, Tomohiko Ishihara, Osamu Onodera

BMC Bioinformatics 24 ( 1 ) 2023年5月

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

Abstract

Background

In the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.

Methods

We analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.

Results

MOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.

Conclusions

MOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.

DOI： 10.1186/s12859-023-05338-5

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その他リンク： https://link.springer.com/article/10.1186/s12859-023-05338-5/fulltext.html

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