Exploring a balancing mechanism between RNA and its binding protein partners

• Project/Area Number: 18H02715
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ishikawa Kinya 東京医科歯科大学, 附属病院, 教授 (30313240)
• Co-Investigator(Kenkyū-buntansha): 柳原 大 東京大学, 大学院総合文化研究科, 教授 (90252725)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: RNA / 小脳 / Purkinje / タンパク / TDP-43 / 脊髄小脳変性症 / ＲＮＡ / ＲＮＡ結合蛋白 / 動物モデル / 神経疾患 / 蛋白質

Outline of Final Research Achievements

This is a study on a mouse model of spinocerebellar ataxia type 3 (SCA31). We established several lines of SCA31 mouse model in which patient-derived bacterial artificial chromosome (BAC) clone was inserted into mouse genome by a conventional transgenesis. We observed a consistent motor phenotype in these mice at around 67 weeks of age. RNA-seq analysis was performed in these mice, which led us to find abnormal gene expressions.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性神経疾患、脊髄小脳変性症「SCA31」の病態を探索する研究である。代表研究者らは2009年にSCA31の原因を発見し、その原因遺伝子部分をマウスに導入して作製したものがSCA31 BAC-Tgである。これまでSCA31のモデルマウスは存在しないため、SCA31 BAC-Tgが、モデルマウスとして妥当かどうかを明らかにすることにもつながる。本研究の結果、このマウスでは患者と同じ遺伝子異常を発現し、67週齢頃に異常な運動症状を表していることが解った。さらに、その病態を明らかにする異常な遺伝子発現状態を確認することができ、SCA31の病態を解明する大きな進歩を果たした。

Research Products

• [Int'l Joint Research] トロント小児病院(カナダ)
• [Int'l Joint Research] ミュンヘン大学(ドイツ)
• [Int'l Joint Research] IGBMC(フランス)
• [Journal Article] Thymidine kinase 2 and mitochondrial protein COX I in the cerebellum of patients with spinocerebellar ataxia type 31 caused by penta-nucleotide repeats (TTCCA) n. (2022)
  • Author(s): Aoki H, Higashi M, Okita M, Ando N, Murayama S, Ishikawa K*, Yokota T.
  • Journal Title: Cerebellum. Volume: Jan 27 Issue: 1 Pages: 70-84
  • DOI: 10.1007/s12311-021-01364-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuropathology of SCA34 showing widespread oligodendroglial pathology with vacuolar white matter degeneration: a case study (2021)
  • Author(s): Ozaki Kokoro、Irioka Takashi、Uchihara Toshiki、Yamada Akane、Nakamura Ayako、Majima Takamasa、Igarashi Susumu、Shintaku Hiroshi、Yakeishi Mayumi、Tsuura Yukio、Okazaki Yasushi、Ishikawa Kinya、Yokota Takanori
  • Journal Title: Acta Neuropathologica Communications Volume: 9 Issue: 1 Pages: 172-172
  • DOI: 10.1186/s40478-021-01272-w
  • Peer Reviewed / Open Access
• [Journal Article] Insight into spinocerebellar ataxia type 31 (SCA31) from Drosophila model. (2021)
  • Author(s): Ishiguro T*, Nagai Y*, Ishikawa K*.
  • Journal Title: Front Neurosci. Volume: 15 Pages: 648133-648133
  • DOI: 10.3389/fnins.2021.648133
  • Peer Reviewed / Open Access
• [Journal Article] Comorbid argyrophilic grain disease in an 87-year-old male with spinocerebellar ataxia type 31 with dementia: a case report (2020)
  • Author(s): S. Toru S. Ishida T. Uchihara K. Hirokawa M. Kitagawa and K. Ishikawa
  • Journal Title: BMC Neurol Volume: 20 Issue: 1 Pages: 136-136
  • DOI: 10.1186/s12883-020-01723-2
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms and future therapeutics for spinocerebrellar ataxia type 31 (SCA31). (2019)
  • Author(s): *Ishikawa K., Nagai Y.
  • Journal Title: Neurotherapeutics Volume: 16 Issue: 4 Pages: 1106-1114
  • DOI: 10.1007/s13311-019-00804-6
  • Peer Reviewed / Open Access
• [Journal Article] RNA結合タンパクと病態機序． (2019)
  • Author(s): 石川欽也、石黒太郎、佐藤望、永井義隆．
  • Journal Title: 脳神経内科 Volume: 91 Pages: 458-464
• [Journal Article] Spinocerebellar Ataxia Type 31 with Blepharospasm (2018)
  • Author(s): Itaya S, Kobayashi Z, Ozaki K, Sato N, Numasawa Y, Ishikawa K, Yokota T, Matsuda H, Shintani S.
  • Journal Title: Internal Medicine Volume: 57 Issue: 11 Pages: 1651-1654
  • DOI: 10.2169/internalmedicine.0068-17
  • NAID: 130007382858
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-06-01
  • Peer Reviewed
• [Journal Article] Tandem internal models execute motor learning in the cerebellum (2018)
  • Author(s): Honda Takeru、Nagao Soichi、Hashimoto Yuji、Ishikawa Kinya、Yokota Takanori、Mizusawa Hidehiro、Ito Masao
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 28 Pages: 7428-7433
  • DOI: 10.1073/pnas.1716489115
  • Peer Reviewed / Open Access
• [Journal Article] A diagnostic decision tree for adult cerebellar ataxia based on pontine magnetic resonance imaging (2018)
  • Author(s): Higashi Miwa、Ozaki Kokoro、Hattori Takaaki、Ishii Takashi、Soga Kazumasa、Sato Nozomu、Tomita Makoto、Mizusawa Hidehiro、Ishikawa Kinya、Yokota Takanori
  • Journal Title: Journal of the Neurological Sciences Volume: 387 Pages: 187-195
  • DOI: 10.1016/j.jns.2018.02.022
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Pathogenesis of spinocerebellar ataxia type 31 (SCA31) (2019)
  • Author(s): 石川欽也．
  • Organizer: 第60回日本神経学会学術大会, 2019/ 5/ 23, 国内, 口頭
  • Invited
• [Presentation] Role of RNA chaperone TDP-43 in the pathogenesis of spinocerebellar ataxia type 31 (SCA31) (2018)
  • Author(s): Kinya Ishikawa
  • Organizer: The 9th International Conference on Unstable Microsatellite and Human Disease.
  • Int'l Joint Research / Invited
• [Book] 日本臨床 増刊号 医薬品副作用学(第3版)下 (2019)
  • Author(s): 石川欽也
  • Total Pages: 545
  • Publisher: 日本臨床社
• [Book] 脊髄小脳変性症・多系統萎縮症診療ガイドライン2018 (2018)
  • Author(s): 日本神経学会・厚生労働省「運動失調症の医薬基盤に関する調査研究班」，「脊髄小脳変性症・多系統萎縮症診療ガイドライン」作成委員会
  • Total Pages: 280
  • Publisher: 南江堂