Elucidation of pathophysiology and development of treatment for spinocerebellar ataxia using a novel mouse model

• Project/Area Number: 18K07503
• 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: Yokohama City University
• Principal Investigator: DOI Hiroshi 横浜市立大学, 医学部, 准教授 (10326035)
• Co-Investigator(Kenkyū-buntansha): 竹内 英之 横浜市立大学, 医学部, 准教授 (30362213) ; 田中 章景 横浜市立大学, 医学研究科, 教授 (30378012) ; 國井 美紗子 横浜市立大学, 医学部, 助教 (80725200)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: spinocerebellar ataxia / mouse model / calcium channel / 脊髄小脳失調症 / 脊髄小脳変性症 / マウスモデル

Outline of Final Research Achievements

Mouse model (Cacna1g_R1723H_KI) with the R1723H variant in Cacna1g corresponding to the R1715H variant of CACNA1G, which is responsible for spinocerebellar ataxia type 42 (SCA42), were developed by genome editing using CRISPR / Cas9. Behavioral analysis confirmed that both heterozygous and homozygous knock-in mice showed ataxia on the rotarod and footprint tests. Pathologically, degeneration of Purkinje cells (PCs) was observed at week 50 in both heterozygous and homozygous knock-in mice. Electrophysiological analysis of the PC revealed a positive shift in the current-voltage curve and a reduced frequency of rebound firing in homozygous knock-in mice. Therefore, we conclude that the SCA42 model has been established. Furthermore, oral administration of T-type VGCC modifier showed improvement in ataxia and PC neurodegeneration in heterozygous knock-in mice.

Academic Significance and Societal Importance of the Research Achievements

SCA分野においては、現時点で有効な疾患修飾治療が存在しない。SCA42自体は希少疾患であるが、本研究ではSCA42の症状を再現するモデルの開発に成功し、チャネル機能修飾治療により失調症状、神経変性が抑制されることを示唆する所見が得た。この結果は、SCAの新たな疾患修飾治療の可能性を示したものと考えられる。

Research Products

• [Journal Article] Hepatitis B Virus-related Vasculitic Neuropathy in an Inactive Virus Carrier Treated with Intravenous Immunoglobulin (2020)
  • Author(s): Kusama Kaori、Nakae Yoshiharu、Tada Mikiko、Higashiyama Yuichi、Miyaji Yosuke、Yamaura Genpei、Kunii Misako、Tanaka Kenichi、Ohyama Ken、Koike Haruki、Joki Hideto、Doi Hiroshi、Koyano Shigeru、Tanaka Fumiaki
  • Journal Title: Internal Medicine Volume: 59 Issue: 23 Pages: 3075-3078
  • DOI: 10.2169/internalmedicine.4498-20
  • NAID: 130007948802
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-12-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-read Sequencing Identifies the Pathogenic Nucleotide Repeat Expansion in RFC1 in a Japanese Case of CANVAS (2020)
  • Author(s): Haruko Nakamura, Hiroshi Doi, Satomi Mitsuhashi, Satoko Miyatake, Kazutaka Katoh, Martin C Frith, Tetsuya Asano, Yosuke Kudo, Takuya Ikeda, Shun Kubota, Misako Kunii, Yu Kitazawa, Mikiko Tada, Mitsuo Okamoto, Hideto Joki, Hideyuki Takeuchi, Naomichi Matsumoto, Fumiaki Tanaka
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 5 Pages: 475-480
  • DOI: 10.1038/s10038-020-0733-y
  • Peer Reviewed / Open Access
• [Journal Article] Reply to "GGC Repeat Expansion of NOTCH2NLC is Rare in European Leukoencephalopathy" (2020)
  • Author(s): Doi H, Okubo M, Fukai R, Fujita A, Mitsuhashi S, Takahashi K, Kunii M, Tada M, Fukuda H, Mizuguchi T, Miyatake S, Miyake N, Sone J, Sobue G, Takeuchi H, Matsumoto N and Tanaka F
  • Journal Title: Ann Neurol Volume: 88 Issue: 3 Pages: 642-643
  • DOI: 10.1002/ana.25819
  • Peer Reviewed
• [Journal Article] De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies (2020)
  • Author(s): Misako Kunii, Hiroshi Doi, Shunta Hashiguchi, Toyojiro Matsuishi, Yasunari Sakai, Mizue Iai, Masaki Okubo, Haruko Nakamura, Keita Takahashi, Atsuko Katsumoto, Mikiko Tada, Hideyuki Takeuchi, Taro Ishikawa, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto, Fumiaki Tanaka
  • Journal Title: Journal of the Neurological Sciences Volume: 416 Pages: 117047-117047
  • DOI: 10.1016/j.jns.2020.117047
  • Peer Reviewed / Open Access
• [Journal Article] CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice. (2020)
  • Author(s): Komiya H, Takeuchi H (責任著者), Ogawa Y, Hatooka Y, Takahashi K, Katsumoto A, Kubota S, Nakamura H, Kunii M, Tada M, Doi H, Tanaka F
  • Journal Title: Molecular Brain Volume: 13 Issue: 1 Pages: 64-64
  • DOI: 10.1186/s13041-020-00607-3
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal clinical manifestations in individuals with COL4A1/2 variants (2020)
  • Author(s): Itai T, Miyatake S, Taguri M, Nakashima M, Saitsu H, Matsumoto N et al.
  • Journal Title: J Med Genet Volume: 0 Issue: 8 Pages: 106896-106896
  • DOI: 10.1136/jmedgenet-2020-106896
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tonsillectomy Improved Therapeutic Response in Anti-SRP Myopathy With Chronic Tonsillitis (2020)
  • Author(s): Ikeda Takuya、Takeuchi Hideyuki、Takahashi Keita、Nakamura Haruko、Kunii Misako、Katsumoto Atsuko、Tada Mikiko、Higashiyama Yuichi、Hibiya Takashi、Suzuki Shigeaki、Nishino Ichizo、Koyano Shigeru、Doi Hiroshi、Tanaka Fumiaki
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 595480-595480
  • DOI: 10.3389/fimmu.2020.595480
  • Peer Reviewed / Open Access
• [Journal Article] CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations (2020)
  • Author(s): Ogasawara M, Iida A, Kumutpongpanich T, Ozaki A, Oya Y, Konishi H, Nakamura A, Abe R, Takai H, Hanajima R, Doi H, Tanaka F, Nakamura H, Nonaka I, Wang Z, Hayashi S, Noguchi S, Nishino I.
  • Journal Title: Acta Neuropathol Commun Volume: 8 Issue: 1 Pages: 204-204
  • DOI: 10.1186/s40478-020-01084-4
  • Peer Reviewed / Open Access
• [Journal Article] Novel <i>VRK1</i> Mutations in a Patient with Childhood-onset Motor Neuron Disease (2019)
  • Author(s): Yamaura Genpei、Higashiyama Yuichi、Kusama Kaori、Kunii Misako、Tanaka Kenichi、Koyano Shigeru、Nakashima Mitsuko、Tsurusaki Yoshinori、Miyake Noriko、Saitsu Hirotomo、Iwahashi Yukiko、Joki Hideto、Matsumoto Naomichi、Doi Hiroshi、Tanaka Fumiaki
  • Journal Title: Internal Medicine Volume: 58 Issue: 18 Pages: 2715-2719
  • DOI: 10.2169/internalmedicine.2126-18
  • NAID: 130007706950
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-09-15
  • Peer Reviewed / Open Access
• [Journal Article] Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42 (2019)
  • Author(s): Hashiguchi S, Doi H, Kunii M, Nakamura Y, Shimuta M, （32名略） Ishikawa T, Tanaka F
  • Journal Title: Neurobiology of Disease Volume: 130 Pages: 104516-104516
  • DOI: 10.1016/j.nbd.2019.104516
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease (2019)
  • Author(s): Sone Jun、Mitsuhashi Satomi et al.
  • Journal Title: Nature Genetics Volume: 51 Issue: 8 Pages: 1215-1221
  • DOI: 10.1038/s41588-019-0459-y
  • Peer Reviewed / Open Access
• [Journal Article] GGC Repeat Expansion of NOTCH2NLC in Adult Patients with Leukoencephalopathy (2019)
  • Author(s): Okubo Masaki、Doi Hiroshi、et al.
  • Journal Title: Annals of Neurology Volume: 86 Issue: 6 Pages: 962-968
  • DOI: 10.1002/ana.25586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteomic analysis of exosome-enriched fractions derived from cerebrospinal fluid of amyotrophic lateral sclerosis patients (2019)
  • Author(s): Hayashi Noriko、Doi Hiroshi、Kurata Yoichi、Kagawa Hiroyuki、Atobe Yoshitoshi、Funakoshi Kengo、Tada Mikiko、Katsumoto Atsuko、Tanaka Kenichi、Kunii Misako、Nakamura Haruko、Takahashi Keita、Takeuchi Hideyuki、Koyano Shigeru、Kimura Yayoi、Hirano Hisashi、Tanaka Fumiaki
  • Journal Title: Neuroscience Research Volume: in press Pages: 30487-0
  • DOI: 10.1016/j.neures.2019.10.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-traumatic Acute Epidural Hematoma in Multiple Sclerosis Treated With Fingolimod (2019)
  • Author(s): Fukai Ryoko、Takahashi Keita、Abe Hiroyuki、Higashiyama Yuichi、Doi Hiroshi、Takeuchi Hideyuki、Tanaka Fumiaki
  • Journal Title: Frontiers in Neurology Volume: 10 Pages: 763-763
  • DOI: 10.3389/fneur.2019.00763
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent NUS1 canonical splice donor site mutation in two unrelated individuals with epilepsy, myoclonus, ataxia and scoliosis - a case report (2019)
  • Author(s): Den Kouhei、Kudo Yosuke、Kato Mitsuhiro、Watanabe Kosuke、Doi Hiroshi、Tanaka Fumiaki、Oguni Hirokazu、Miyatake Satoko、Mizuguchi Takeshi、Takata Atsushi、Miyake Noriko、Mitsuhashi Satomi、Matsumoto Naomichi
  • Journal Title: BMC Neurology Volume: 19 Issue: 1 Pages: 253-253
  • DOI: 10.1186/s12883-019-1489-x
  • Peer Reviewed / Open Access
• [Journal Article] Adult-onset vocal cord paralysis in slow-channel congenital myasthenic syndrome (2019)
  • Author(s): Nakamura Haruko、Komiya Hiroyasu、Uematsu Eri、Nakae Yoshiharu、Tanaka Kenichi、Kunii Misako、Tada Mikiko、Joki Hideto、Koyano Shigeru、Matsumoto Naomichi、Doi Hiroshi、Takeuchi Hideyuki、Tanaka Fumiaki
  • Journal Title: Neurology: Clinical Practice Volume: 9 Issue: 5
  • DOI: 10.1212/cpj.0000000000000599
  • Peer Reviewed / Open Access
• [Journal Article] Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations (2018)
  • Author(s): Doi H、Koyano S、Miyatake S、Nakajima S、Nakazawa Y、Kunii M、Tomita-Katsumoto A、Oda K、Yamaguchi Y、Fukai R、Ikeda S、Kato R、Ogata K、Kubota S、Hayashi N、Takahashi K、Tada M、Tanaka K、Nakashima M、Tsurusaki Y et al.
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 4 Pages: 417-423
  • DOI: 10.1038/s10038-017-0408-5
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel (2018)
  • Author(s): Kunii M.、Doi H.、Ishii Y.、Ohba C.、Tanaka K.、Tada M.、Fukai R.、Hashiguchi S.、Kishida H.、Ueda N.、Kudo Y.、Kugimoto C.、Nakano T.、Udaka N.、Miyatake S.、Miyake N.、Saitsu H.、Ito Y.、Takahashi K.、Nakamura H.、Tomita-Katsumoto A.、Takeuchi H.、Koyano S.、Matsumoto N.、Tanaka F.
  • Journal Title: Clinical Genetics Volume: - Issue: 2 Pages: 232-238
  • DOI: 10.1111/cge.13371
  • Peer Reviewed
• [Journal Article] White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease (2018)
  • Author(s): Joki Hideto、Higashiyama Yuichi、Nakae Yoshiharu、Kugimoto Chiharu、Doi Hiroshi、Kimura Katsuo、Kishida Hitaru、Ueda Naohisa、Nakano Tatsu、Takahashi Tatsuya、Koyano Shigeru、Takeuchi Hideyuki、Tanaka Fumiaki
  • Journal Title: Journal of the Neurological Sciences Volume: 385 Pages: 99-104
  • DOI: 10.1016/j.jns.2017.12.018
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral olfactory tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation (2018)
  • Author(s): Takahashi Keita、Takeuchi Hideyuki、Kurihara Yuji、Doi Hiroshi、Kunii Misako、Tanaka Kenichi、Nakamura Haruko、Fukai Ryoko、Tomita-Katsumoto Atsuko、Tada Mikiko、Higashiyama Yuichi、Joki Hideto、Koyano Shigeru、Takei Kohtaro、Tanaka Fumiaki
  • Journal Title: Journal of Neuroinflammation Volume: 15 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s12974-018-1084-x
  • Peer Reviewed / Open Access
• [Journal Article] Two cases of anaphylactic shock by methylprednisolone in neuromyelitis optica (2018)
  • Author(s): Takahashi Keita、Asano Tetsuya、Higashiyama Yuichi、Koyano Shigeru、Doi Hiroshi、Takeuchi Hideyuki、Tanaka Fumiaki
  • Journal Title: Multiple Sclerosis Journal Volume: 24 Issue: 11 Pages: 1514-1516
  • DOI: 10.1177/1352458518763099
  • NAID: 120006808928
  • Peer Reviewed
• [Journal Article] Biallelic COLGALT1 variants are associated with cerebral small vessel disease (2018)
  • Author(s): Miyatake Satoko、Schneeberger Sacha、Koyama Norihisa、Yokochi Kenji、Ohmura Kayo、、Hennet Thierry、Matsumoto Naomichi、et al
  • Journal Title: Annals of Neurology Volume: 84 Issue: 6 Pages: 843-853
  • DOI: 10.1002/ana.25367
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Confirmation of SLC5A7-related distal hereditary motor neuropathy 7 in a family outside Wales (2018)
  • Author(s): Hamanaka K.、Takahashi K.、Miyatake S.、Mitsuhashi S.、Hamanoue H.、Miyaji Y.、Fukai R.、Doi H.、Fujita A.、Imagawa E.、Iwama K.、Nakashima M.、Mizuguchi T.、Takata A.、Miyake N.、Takeuchi H.、Tanaka F.、Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 94 Issue: 2 Pages: 274-275
  • DOI: 10.1111/cge.13369
  • Peer Reviewed
• [Journal Article] A Japanese Family of Spinocerebellar Ataxia Type 21: Clinical and Neuropathological Studies (2018)
  • Author(s): Yahikozawa Hiroyuki、Miyatake Satoko、Sakai Toshiaki、Uehara Takeshi、Yamada Mitsunori、Hanyu Norinao、Futatsugi Yasuhiro、Doi Hiroshi、Koyano Shigeru、Tanaka Fumiaki、Suzuki Atsushi、Matsumoto Naomichi、Yoshida Kunihiro
  • Journal Title: The Cerebellum Volume: 印刷中 Issue: 5 Pages: 525-530
  • DOI: 10.1007/s12311-018-0941-6
  • Peer Reviewed
• [Journal Article] 【もっとうまくいく！病診連携の「伝え方」 わかりやすく伝えるための診療情報提供書作成のコツ】第II章＜診療科別＞コンサルトのポイント E. 脳神経内科へのコンサルト 歩行障害． (2018)
  • Author(s): 土井 宏、田中 章景
  • Journal Title: 内科 Volume: 122 Pages: 564-566
• [Journal Article] 【ニューロジェネティクス新時代 次世代シークエンサーが拓く新しい世界】 筋疾患・神経疾患のジェネティクス 筋萎縮性側索硬化症. (2018)
  • Author(s): 土井 宏、田中 章景
  • Journal Title: Clinical Neuroscience Volume: 36 Pages: 206-209
• [Journal Article] 【中枢神経疾患における末梢神経障害】 有棘赤血球舞踏病における末梢神経障害. (2018)
  • Author(s): 土井 宏、田中 章景
  • Journal Title: 神経内科 Volume: 89 Pages: 457-462
• [Presentation] Genetic analysis of adult leukoencephalopathies (2020)
  • Author(s): 土井宏，大久保正紀，深井綾子，國井美紗子，岸田日帯，高橋慶太，勝元敦子，多田美紀子，藤田京志，三橋里美，宮武聡子，伊藤泰広， 上田直久，児矢野繁，竹内英之，松本直通，田中章景
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42 (2020)
  • Author(s): 橋口俊太，土井宏，國井美紗子，中村行宏，志牟田美佐，鈴木江津子，大久保正紀, 窪田瞬，多田美紀子，児矢野繁，竹内英之，石川太郎，田中章景
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42. (2019)
  • Author(s): Hiroshi Doi, Shunta Hashiguchi, Misako Kunii, Yukihiro Nakamura, Misa Shimuta, Etsuko Suzuki, Masaki Okubo, Toshikuni Sasaoka, Hideyuki Takeuchi, Taro Ishikawa, Fumiaki Tanaka
  • Organizer: Neuroscience 2019
  • Int'l Joint Research
• [Presentation] Clinical characteristics of four patients with ERCC4 mutations manifesting ataxia phenotype. (2018)
  • Author(s): 土井 宏, 児矢野繁, 宮武聡子, 中島伸二, 中沢由華, 國井美紗子, 勝元敦子, 深井綾子, 荻朋男, 竹内英之, 松本直通, 田中章景
  • Organizer: 第59回日本神経学会学術大会