Elucidation of the ALS/FTLD pathomechanism mediated by the dysfunction of ribosome biogenesis

• Project/Area Number: 18K06705
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Suzuki Hiroaki 東京医科大学, 医学部, 講師 (10424178)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / C9orf72遺伝子変異 / 神経変性疾患 / 前頭側頭型認知症 / 神経細胞死 / RNA編集 / ADAR / C9ORF72遺伝子変異 / パラスペックル / NEAT1 / リボソーム生合成 / RNAヘリカーゼ / C9ORF72 / リボソーム

Outline of Final Research Achievements

I investigated the pathomechanism underlying C9orf72-linked amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In the current study, I found that poly-PR, a dipeptide repeat protein derived from C9orf72 mutation, causes neuronal cell death by inhibiting the ribosome biogenesis, paraspeckles, and RNA editing.

Academic Significance and Societal Importance of the Research Achievements

ALS/FTLDの発症メカニズムを両疾患において最も高頻度に認められるC9orf72遺伝子変異に着目し解析した。本研究の遂行により、複数の神経細胞死メカニズムが明らかになり、本研究の成果は両疾患の理解を深めると共に、新たな創薬ターゲットの同定に結びつくものであり、超高齢化社会を迎え、両疾患の根本的治療薬が望まれる我が国において、医学的社会的意義のある成果が得られた。

Research Products

• [Journal Article] C9-ALS/FTD-linked proline-arginine dipeptide repeat protein associates with paraspeckle components and increases paraspeckle formation (2019)
  • Author(s): Suzuki Hiroaki、Shibagaki Yoshio、Hattori Seisuke、Matsuoka Masaaki
  • Journal Title: Cell Death & Disease Volume: 10 Issue: 10 Pages: 746-746
  • DOI: 10.1038/s41419-019-1983-5
  • Peer Reviewed / Open Access
• [Journal Article] The proline-arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis (2018)
  • Author(s): Hiroaki Suzuki, Yoshio Shibagaki, Seisuke Hattori, Masaaki Matsuoka
  • Journal Title: Cell Death & Disease Volume: 9 Issue: 10 Pages: 975-975
  • DOI: 10.1038/s41419-018-1028-5
  • Peer Reviewed / Open Access
• [Presentation] C9-ALS/FTD-linked proline-arginine dipeptide repeat protein inhibits adenosine deaminase acting on RNA (2021)
  • Author(s): Suzuki Hiroaki、Matsuoka Masaaki
  • Organizer: 第94回日本薬理学会年会
• [Presentation] C9-ALS/FTD-linked proline-arginine dipeptide repeat protein causes neuronal cell death by associating with paraspeckle components (2020)
  • Author(s): Suzuki Hiroaki、Matsuoka Masaaki
  • Organizer: 第93回日本薬理学会年会
• [Presentation] C9-ALS/FTD-linked proline-arginine dipeptide repeat protein causes neurotoxicity by disrupting paraspeckle integrity (2020)
  • Author(s): Suzuki Hiroaki、Matsuoka Masaaki
  • Organizer: 第43回日本神経科学大会
• [Presentation] C9ORF72-linked proline-arginine dipeptide repeat protein inhibits RNA helicase-mediated ribosome biogenesis and causes neurotoxicity (2019)
  • Author(s): 鈴木宏昌、松岡正明
  • Organizer: 第92回日本薬理学会年会
• [Presentation] The proline-arginine repeat protein linked to C9ORF72-ALS/FTD inhibits RNA helicase-mediated ribosome biogenesis and causes neuronal cell death (2018)
  • Author(s): Hiroaki Suzuki, Masaaki Matsuoka
  • Organizer: Society for Neuroscience 2018, SfN's 48th Annual Meeting
  • Int'l Joint Research
• [Remarks] 東京医科大学医学部医学科薬理学分野
  • URL: http://www.tokyo-med.ac.jp/pharmacol/top.html