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Misregulation of KIF1A in motor neuron disease

Research Project

Project/Area Number 17KK0139
Research Category

Fund for the Promotion of Joint International Research (Fostering Joint International Research)

Allocation TypeMulti-year Fund
Research Field Morphology/Structure
Research InstitutionTohoku University

Principal Investigator

Niwa Shinsuke  東北大学, 学際科学フロンティア研究所, 准教授 (30714985)

Project Period (FY) 2017 – 2019
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
Keywords軸索輸送 / KIF1A / 遺伝性痙性対麻痺 / キネシン / UNC-104 / kinesin / 神経 / 疾患 / 痙性対麻痺
Outline of Final Research Achievements

KIF1A is a motor protein involved in the axonal transport of synaptic vesicles along microtubules. Mutations in KIF1A are associated with the motor neuron disease. However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus, a molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this project, we established in vitro motility assays with full-length human KIF1A and found that KIF1A mutations associated with the motor neuron disease lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into Caenorhabditis elegans KIF1A homologue revealed abnormal accumulation of synaptic vesicles at the tips of axons. This project revealed that hyperactivation of kinesin motor activity is a novel cause of motor neuron disease.

Academic Significance and Societal Importance of the Research Achievements

正しい治療法のためには正しい原因解明が必須である。これまでは軸索輸送の低下が神経疾患の原因となると考えられてきた。しかし、この研究によってはじめて、今までの常識とは逆に、軸索輸送の亢進もまたヒト神経疾患の原因となりうることが示された。近年の全ゲノムシークエンス技術の発達により、KIF1Aの点変異が先天性神経疾患のホットスポットの一つであることが分かってきている。本研究で得られた成果により、そのような神経疾患でみられる変異がKIF1Aの機能の低下を起こしているか、亢進を起こしているかを調べることが治療方針を立てる上で重要であることがわかった。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (10 results)

All 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (6 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results) Remarks (1 results)

  • [Int'l Joint Research] カリフォルニア大学デービス校(米国)2018

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors2019

    • Author(s)
      Chiba Kyoko、Takahashi Hironori、Chen Min、Obinata Hiroyuki、Arai Shogo、Hashimoto Koichi、Oda Toshiyuki、McKenney Richard J.、Niwa Shinsuke
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 37 Pages: 18429-18434

    • DOI

      10.1073/pnas.1905690116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Going Too Far Is the Same as Falling Short†: Kinesin-3 Family Members in Hereditary Spastic Paraplegia2019

    • Author(s)
      Gabrych Dominik R.、Lau Victor Z.、Niwa Shinsuke、Silverman Michael A.
    • Journal Title

      Frontiers in Cellular Neuroscience

      Volume: 13

    • DOI

      10.3389/fncel.2019.00419

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Disease-associated mutations in human KIF1A overactivate motility of KIF1A and anterograde axonal transport of synaptic vesicle precursors2019

    • Author(s)
      Chiba K, Takahashi H, Chen M, Obinata H, Arai S, Hashimoto K, Oda T, McKenney RJ, Niwa S
    • Organizer
      分子生物学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Disease-associated mutations in human KIF1A overactivate motility of KIF1A and anterograde axonal transport of synaptic vesicle precursors2019

    • Author(s)
      丹羽伸介
    • Organizer
      神経科学学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The regulation of axonal transport and motor neuron disease2019

    • Author(s)
      丹羽伸介
    • Organizer
      北京大学生物科学セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The regulation of axonal transport and motor neuron disease2019

    • Author(s)
      丹羽伸介
    • Organizer
      清華大学セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Motor disease mutations in human KIF1A disrupt autoinhibition of KIF1A motor2018

    • Author(s)
      Kyoko Chiba, Richard J. McKenney, Shinsuke Niwa
    • Organizer
      American Society for Cell Biology (ASCB)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Motor disease mutations in human KIF1A disrupt autoinhibition of KIF1A motor2018

    • Author(s)
      Kyoko Chiba, Richard J. McKenney, Shinsuke Niwa
    • Organizer
      EMBL Symposium "Microtubule: From Atoms to Complex Systems"
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] 運動神経疾患の新たな原因を発見 細胞内のトラックの暴走が疾患を引き起こす

    • URL

      https://www.fris.tohoku.ac.jp/feature/topics/detail---id-631.html

    • Related Report
      2019 Annual Research Report

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Published: 2018-01-25   Modified: 2021-02-19  

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