Elucidation of the molecular mechanisms of dopaminergic neurodegenerative disorders using a large genome resource

• Project/Area Number: 19K08003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Funayama Manabu 順天堂大学, 医学部, 先任准教授 (70468578)
• Co-Investigator(Kenkyū-buntansha): 斉木 臣二 順天堂大学, 医学部, 先任准教授 (00339996) ; 村上 晶 順天堂大学, 医学部, 教授 (90157743)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: パーキンソン病 / 網膜色素変性症 / 次世代シーケンサー / 原因遺伝子 / オートファジー / 遺伝子 / ドーパミン / 神経細胞変性 / エクソーム / iPS細胞 / 神経細胞死 / ゲノム

Outline of Research at the Start

パーキンソン病 (PD) は運動症状に加え認知症などの非運動症状もしばしば併発し、その1つとして色覚異常が指摘されている。網膜には5種類の神経細胞があり、その全てにドーパミ ンが作用する。近年、網膜における菲薄化やαシヌクレインの蓄積がPDの早期バイオマー カーとなる可能性が臨床的・病理学的観察から示されているが分子遺伝学的な報告は無い。 本研究ではPDと網膜色素変性症 (RP) を合併する濃厚な家系を6家系について原因遺伝子を同定すると共に、PDとRPの遺伝的相互作用、さらには分子病態機能を明らかにするためにiPS細胞を使い脳と網膜の特徴を有するドーパミン神経細胞分化法を開発する。

Outline of Final Research Achievements

We performed a whole exome sequencing (WES) of six families with Parkinson's disease (PD) complicated by retinitis pigmentosa (RP). We have successfully improved the efficiency of candidate variants filtering using the gene list obtained from the MIMmatch database. We identified a disease-specific gene X in one family by WES. Gene X was validated using genomic DNA from 1,029 PD or hereditary eye disease patients by Sanger sequencing, and rare variants were detected in three autosomal dominant PD and 17 patients with sporadic PD. Most of the PD patients with rare variants in gene X were young-onset PD with age of onset less than 50 years.

Academic Significance and Societal Importance of the Research Achievements

本研究で発見された遺伝子XはすでにPD以外の神経変性疾患において発症原因となることが報告されている、したがって、遺伝子Xにおいて若年発症常染色体顕性遺伝性PDという新たな表現型を定義することができ、遺伝子X関連疾患スペクトラムという新しい概念を提唱することが可能となった意味で本研究の意義は大きい。遺伝子Xは細胞内分解システムであるオートファジー・リソソーム系において重要な役割を演じているタンパク質をコードしていることはすでに明らかとなっており、今後モデル細胞やモデル動物を使った病態生理機能解析を推進することでPDの新しい診断や治療法の開発に寄与することが可能であると考えられる。

Research Products

• [Journal Article] Loss of <i>Atg2b</i> and <i>Gskip</i> Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size (2022)
  • Author(s): Sakai Shun-suke、Hasegawa Atsushi、Ishimura Ryosuke、Tamura Naoki、Kageyama Shun、Komatsu-Hirota Satoko、Abe Manabu、Ling Yiwei、Okuda Shujiro、Funayama Manabu、Kikkawa Mika、Miura Yoshiki、Sakimura Kenji、Narita Ichiei、Waguri Satoshi、Shimizu Ritsuko、Komatsu Masaaki
  • Journal Title: Molecular and Cellular Biology Volume: 42 Issue: 1 Pages: 1-17
  • DOI: 10.1128/mcb.00024-21
  • Peer Reviewed / Open Access
• [Journal Article] A complex form of hereditary spastic paraplegia harboring a novel variant, p.W1515*, in the SPG11 gene (2022)
  • Author(s): Daida Kensuke、Nishioka Yosuke、Li Yuanzhe、Yoshino Hiroyo、Funayama Manabu、Hattori Nobutaka、Nishioka Kenya
  • Journal Title: eNeurologicalSci Volume: 26 Pages: 100391-100391
  • DOI: 10.1016/j.ensci.2021.100391
  • Peer Reviewed / Open Access
• [Journal Article] Deep Brain Stimulation for a Patient with Familial Parkinson's Disease Harboring CHCHD2 p.T61I. (2022)
  • Author(s): Kamo Hikaru、Oyama Genko、Nishioka Kenya、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Movement Disorders Clinical Practice Volume: 9 Issue: 3 Pages: 407-409
  • DOI: 10.1002/mdc3.13428
  • Peer Reviewed / Open Access
• [Journal Article] Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice (2021)
  • Author(s): Sato Shigeto、Noda Sachiko、Torii Satoru、Amo Taku、Ikeda Aya、Funayama Manabu、Yamaguchi Junji、Fukuda Takahiro、Kondo Hiromi、Tada Norihiro、Arakawa Satoko、Watanabe Masahiko、Uchiyama Yasuo、Shimizu Shigeomi、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 30 Issue: 6 Pages: 443-453
  • DOI: 10.1093/hmg/ddab057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic analysis of ATP10B for Parkinson's disease in Japan (2021)
  • Author(s): Ishiguro Mayu、Yoshino Hiroyo、Li Yuanzhe、Ikeda Aya、Funayama Manabu、Nishioka Kenya、Hattori Nobutaka
  • Journal Title: Parkinsonism and Related Disorders Volume: 88 Pages: 10-12
  • DOI: 10.1016/j.parkreldis.2021.05.020
  • Peer Reviewed
• [Journal Article] Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network (2021)
  • Author(s): Mathys Grapotte, Manu Saraswat, Chloe Bessiere, and all 474 authors, Laurent Brehelin
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3297-3297
  • DOI: 10.1038/s41467-021-23143-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The East Asian Parkinson Disease Genomics Consortium (2021)
  • Author(s): Mok Kin Y、、、Funayama Manabu、、et al.
  • Journal Title: The Lancet Neurology Volume: 20 Issue: 12 Pages: 982-982
  • DOI: 10.1016/s1474-4422(21)00373-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PLA2G6 variants associated with the number of affected alleles in Parkinson’s disease in Japan (2021)
  • Author(s): Daida Kensuke、Nishioka Kenya、Li Yuanzhe、Yoshino Hiroyo、Shimada Tomoyo、Dougu Nobuhiro、et al.
  • Journal Title: Neurobiology of Aging Volume: 97 Pages: 1-9
  • DOI: 10.1016/j.neurobiolaging.2020.07.004
  • Peer Reviewed
• [Journal Article] Clinical manifestations of Parkinson's disease harboring VPS35 retromer complex component p.D620N with long-term follow-up (2021)
  • Author(s): Ishiguro Mayu、Li Yuanzhe、Yoshino Hiroyo、Daida Kensuke、Ishiguro Yuta、Oyama Genko、Saiki Shinji、Funayama Manabu、Hattori Nobutaka、Nishioka Kenya
  • Journal Title: Parkinsonism & Related Disorders Volume: 84 Pages: 139-143
  • DOI: 10.1016/j.parkreldis.2021.02.014
  • Peer Reviewed
• [Journal Article] The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1 (2021)
  • Author(s): Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Daida Kensuke、Ikeda Aya、et al.
  • Journal Title: Neurobiology of Aging Volume: 97 Pages: 3301-3301
  • DOI: 10.1016/j.neurobiolaging.2020.06.017
  • Peer Reviewed / Open Access
• [Journal Article] Shared Metabolic Profile of Caffeine in Parkinsonian Disorders (2020)
  • Author(s): Takeshige‐Amano Haruka、Saiki Shinji、Fujimaki Motoki、Ueno Shin‐Ichi、Li Yuanzhe、Hatano Taku、Ishikawa Kei‐Ichi、Oji Yutaka、Mori Akio、Okuzumi Ayami、Tsunemi Taiji、Daida Kensuke、Ishiguro Yuta、Imamichi Yoko、Nanmo Hisayoshi、Nojiri Shuko、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 35 Issue: 8 Pages: 1438-1447
  • DOI: 10.1002/mds.28068
  • Peer Reviewed / Open Access
• [Journal Article] Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease (2020)
  • Author(s): Yamaguchi Akihiro、Ishikawa Kei-ichi、Inoshita Tsuyoshi、Shiba-Fukushima Kahori、Saiki Shinji、Hatano Taku、Mori Akio、Oji Yutaka、Okuzumi Ayami、Li Yuanzhe、Funayama Manabu、Imai Yuzuru、Hattori Nobutaka、Akamatsu Wado
  • Journal Title: Stem Cell Reports Volume: 14 Issue: 6 Pages: 1060-1075
  • DOI: 10.1016/j.stemcr.2020.04.011
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Disease-Associated Variants by Targeted Gene Panel Resequencing in Parkinson's Disease (2020)
  • Author(s): Daida Kensuke、Funayama Manabu、Li Yuanzhe、Yoshino Hiroyo、Hayashida Arisa、Ikeda Aya、Ogaki Kotaro、Nishioka Kenya、Hattori Nobutaka
  • Journal Title: Frontiers in Neurology Volume: 11 Pages: 576465-576465
  • DOI: 10.3389/fneur.2020.576465
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy (2020)
  • Author(s): Lin Chin-Hsien、Tsai Pei-I、Lin Han-Yi、Hattori Nobutaka、Funayama Manabu、Jeon Beomseok、et al.
  • Journal Title: Brain Volume: 143 Issue: 11 Pages: 3352-3373
  • DOI: 10.1093/brain/awaa279
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease (2020)
  • Author(s): Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, et al.
  • Journal Title: Brain Volume: 143 Issue: 4 Pages: 1190-1205
  • DOI: 10.1093/brain/awaa064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutations in CHCHD2 cause α-synuclein aggregation (2019)
  • Author(s): Ikeda A., Nishioka K., Meng H., Takanashi M., Hasegawa I., Inoshita T., Shiba-Fukushima K., Li Y., Yoshino H., Mori A., Okuzumi A., Yamaguchi A., Nonaka R., Izawa N., Ishikawa K.I., Saiki H., Morita M., Hasegawa M., Hasegawa K., Elahi M., et al.
  • Journal Title: Human Molecular Genetics Volume: 28 Issue: 23 Pages: 3895-3911
  • DOI: 10.1093/hmg/ddz241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutation analysis of LRP10 in Japanese patients with familial Parkinson’s disease, progressive supranuclear palsy, and fronto-temporal dementia (2019)
  • Author(s): Daida K, Nishioka K, Li Y, Yoshino H, Kikuchi A, Hasegawa T, Funayama M, Hattori N
  • Journal Title: Neurobiol Aging Volume: 84 Pages: 235.e11-235.e16
  • DOI: 10.1016/j.neurobiolaging.2019.08.030
  • Peer Reviewed
• [Journal Article] Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone. (2019)
  • Author(s): J. S. Lee, K. Kanai, M. Suzuki, W. S. Kim, H. S. Yoo, Y. Fu, D-K. Kim, B. C. Jung, M. Choi, K. W. Oh, Y. Li, M. Nakatani, T. Nakazato, S. Sekimoto, M. Furuyama, H. Yoshino, S. Kubo, K. Nishioka, R. Sakai, M. Ueyama, H. Mochizuki, H-J. Lee, S. P. Sardi, G. M. Halliday, Y. Nagai, P. H. Lee, N. Hattori, S-J. Lee
  • Journal Title: Brain Volume: 142 Issue: 9 Pages: 2845-59
  • DOI: 10.1093/brain/awz205
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Using global team science to identify genetic parkinson's disease worldwide (2019)
  • Author(s): Vollstedt E.J., Kasten M., Klein C., Group M.G.G.P.s.D.S.
  • Journal Title: Annals of Neurology Volume: 86 Issue: 2 Pages: 153-157
  • DOI: 10.1002/ana.25514
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features (2019)
  • Author(s): Ikeda Aya、Shimada Hitoshi、Nishioka Kenya、Takanashi Masashi、Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Funayama Manabu、Ueno Yuji、Hatano Taku、Sahara Naruhiko、Suhara Tetsuya、Higuchi Makoto、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 34 Issue: 4 Pages: 568-574
  • DOI: 10.1002/mds.27623
  • Peer Reviewed / Open Access
• [Journal Article] A metabolic profile of polyamines in parkinson disease: A promising biomarker (2019)
  • Author(s): Saiki Shinji、Sasazawa Yukiko、Fujimaki Motoki、Kamagata Koji、Kaga Naoko、Taka Hikari、Li Yuanzhe、Souma Sanae、Hatano Taku、Imamichi Yoko、Furuya Norihiko、Mori Akio、Oji Yutaka、Ueno Shin‐Ichi、Nojiri Shuko、Miura Yoshiki、Ueno Takashi、Funayama Manabu、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Annals of Neurology Volume: 86 Issue: 2 Pages: 251-263
  • DOI: 10.1002/ana.25516
  • Peer Reviewed / Open Access
• [Presentation] パーキンソン病の分子遺伝学―近年の解析の動向― (2021)
  • Author(s): 舩山学
  • Organizer: 高松国際パーキンソン病シンポジウム in Tokyo 2022
  • Int'l Joint Research / Invited
• [Presentation] Identification of common molecular mechanism between Parkinson’s disease and Retinitis pigmentosa. (2021)
  • Author(s): 舩山学，斉木臣二，吉野浩代，李元哲，西岡健弥，服部信孝
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] Causative gene finding for families with Parkinson's disease and Retinitis pigmentosa by whole exome sequencing. (2021)
  • Author(s): 舩山学, 斉木臣二, 代田健祐, 吉野浩代, 李元哲, 西岡健弥, 服部信孝
  • Organizer: 日本人類遺伝学会第66回大会
• [Presentation] SH-SY5YにおけるCHCHD8欠損によるミトコンドリア呼吸鎖複合体IVの機能不全 (2021)
  • Author(s): 日景勇賀, 永沼陸, 古本菜々子, 舩山学, 服部信孝, 天羽拓
  • Organizer: 第20回日本ミトコンドリア学会 年会
• [Presentation] 22q11.2 deletion syndrome among the patients with early-onset Parkinson's disease. (2021)
  • Author(s): Yuki Mangyoku, Manabu Funayama, Yuanzhe Li, Hiroyo Yoshino, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] The frequency of 22q11.2 deletion among the patients with early-onset Parkinson's disease. (2021)
  • Author(s): Yuki Mangyoku, Manabu Funayama, Yuanzhe Li, Hiroyo Yoshino, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 日本人類遺伝学会第66回大会
• [Presentation] Analysis of genetic testing for spinocerebellar ataxia (2020)
  • Author(s): 櫻井麻由、土屋浩二、吉野浩代、舩山 学、田部陽子、西岡健弥、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Next-generation sequencing expand the possibilities to detect more variants in Parkinson's disease (2020)
  • Author(s): 李 元哲、吉野浩代、舩山 学、戸田達史、西岡健弥、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] PINK1 heterozygote変異はalpha-synucleinopathyに部分的に関与する (2020)
  • Author(s): 西岡健弥、李 元哲、林田有紗、代田健祐、池田 彩、大垣光太郎、吉野浩代、舩山 学、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Identifying a novel causative gene associated with familial Parkinson's disease (2020)
  • Author(s): 代田健祐、舩山 学、李 元哲、吉野浩代、林田有紗、池田 彩、大垣光太郎、西岡健弥、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Mutational and functional analysis of the CHCHD2 gene in amyotrophic lateral sclerosis (2020)
  • Author(s): 池田 彩、舩山 学、吉田眞理、李 元哲、饗場郁子、齋藤由扶子、熱田直樹、中村亮一、藤内玄規、曽根 淳、和泉唯信、梶 龍兒、森田光哉、谷口 彰、祖父江 元、服部信孝、JaCALS
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Clinicogenetic study on mono-allelic and bi-allelic mutation of PLA2G6 in Parkinson’s disease (2019)
  • Author(s): Manabu Funayama, Hiroyo Yoshino, Yuanzhe Li, Yasushi Shimo, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Comparison of clinical phenotype between mono-allelic and bi-allelic mutation of PLA2G6 in Parkinson’s disease. (2019)
  • Author(s): 舩山学、吉野浩代、李元哲、下泰司、西岡健弥、服部信孝
  • Organizer: 第13回パーキンソン病・運動障害疾患コングレス
• [Book] 順天堂大脳神経内科ではこうしている 最新 パーキンソン病診療【電子版付】 (2021)
  • Author(s): 服部信孝(編著)、舩山学(分担執筆)
  • Total Pages: 224
  • Publisher: 日本医事新報社
  • ISBN: 9784784949502
• [Remarks] ライソゾーム病の原因遺伝子がパーキンソン病の発症に関わることを発見
  • URL: https://www.juntendo.ac.jp/news/20200323-01.html
• [Remarks] ライソゾーム病とパーキンソン病の共通分子を発見
  • URL: https://www.juntendo.ac.jp/news/20190724-01.html