Elucidation of molecular pathomechanism of TDP-43 and FUS-linked ALS

• Project/Area Number: 25460342
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: Suzuki Hiroaki 東京医科大学, 医学部, 助教 (10424178)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 筋萎縮性側索硬化症 / 神経細胞死 / TDP-43 / FUS / hnRNP / hnRNPA1 / 神経変性疾患 / 前頭側頭葉変性症

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is an incurable adult-onset motor neuron degenerative disease, characterized by loss of both upper and lower motor neurons.
In this study, we focused on RNA-biniding proteins (RBPs) including TDP-43, FUS, and hnRNPA1 that are thought to be closely linked to the pathogenesis of ALS. We elucidated the molecular pathomechanisms underlying RBPs-induced neuronal cell death.
We have plans to develop therapeutic drugs for ALS that target RBPs-related neuronal cell death.

Research Products

• [Journal Article] Nuclear TDP-43 causes neuronal toxicity by escaping from the inhibitory regulation by hnRNPs (2015)
  • Author(s): Hiroaki Suzuki, Yoshio Shibagaki, Seisuke Hattori, and Masaaki Matsuoka
  • Journal Title: Human Molecular Genetics Volume: 24 Issue: 6 Pages: 1513-1527
  • DOI: 10.1093/hmg/ddu563
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of nuclear FUS induces neuronal cell death (2015)
  • Author(s): Hiroaki Suzuki and Masaaki Matsuoka
  • Journal Title: Neuroscience Volume: 287 Pages: 113-124
  • DOI: 10.1016/j.neuroscience.2014.12.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The effect of self-training in advance using an e-learning system on pharmacological practice (2015)
  • Author(s): Ichie Hara, Hiroaki Suzuki, Shinya Kusakari, and Masaaki Matsuoka
  • Journal Title: Folia Pharmacologica Japonica Volume: 145 Issue: 2 Pages: 80-84
  • DOI: 10.1254/fpj.145.80
  • NAID: 130004827723
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Presentation] hnRNPA1のALS/MSP変異体は自己発現調節機構の異常により細胞毒性を示す (2016)
  • Author(s): 鈴木宏昌、松岡正明
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-10
• [Presentation] Nuclear TDP-43 causes neuronal toxicity by overcoming the intrinsic cell death -preventing mechanism mediated by hnRNPs (2015)
  • Author(s): Hiroaki Suzuki, Yoshio Shibagaki, Seisuke Hattori, and Masaaki Matsuoka
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-03-20
• [Presentation] Nuclear TDP-43 induces neuronal cell death by associating with heterogeneous nuclear ribonucleoprotein-U (2014)
  • Author(s): Hiroaki Suzuki and Masaaki Matsuoka
  • Organizer: Society for Neuroscience 2014
  • Place of Presentation: Washington, DC
  • Year and Date: 2014-11-17