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Structurally distinct alpha-synuclein fibrils induce robust Parkinsonian pathology

Research Project

Project/Area Number 16K19512
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Neurology
Research InstitutionOsaka University

Principal Investigator

Hayakawa Hideki  大阪大学, 医学系研究科, 特任研究員 (70468594)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywordsパーキンソン病 / alpha-synuclein / α-synuclein / 多系統萎縮症 / オリゴデンドロサイト / 脳神経疾患 / 脳・神経
Outline of Final Research Achievements

Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson’s disease, and its genetic mutations cause familial forms of Parkinson’s disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. We found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病(PD)は神経変性疾患の中でアルツハイマー病についで2番目に多く、高齢化社会を迎える本邦に限らず、世界的に患者数の増加が予想される。現状では有効な予防法や根治療法はなく、その病態の解明と治療法の開発は医学研究の急務となっている。PDの治療研究における問題点は、病態を反映した優れたPDモデルが無いことであった。そのために、治療開発が大きく遅れており、その開発が急務である。我々は変異αシヌクレイン(αsyn) fibrilを用い、リン酸化αsyn(p-αsyn)凝集と黒質ドパミン(DA)神経細胞の変性脱落、それに伴う運動機能低下を有意に認める新規PDモデルマウスを作成し報告した。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2019 2018 2017 2016

All Journal Article (3 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: 1 results)

  • [Journal Article] Structurally Distinct α‐Synuclein Fibrils Induce Robust Parkinsonian Pathology2019

    • Author(s)
      Hayakawa Hideki、Nakatani Rie、Ikenaka Kensuke、Aguirre Cesar、Choong Chi‐Jing、Tsuda Hiroshi、Nagano Seiichi、Koike Masato、Ikeuchi Takeshi、Hasegawa Masato、Papa Stella M.、Nagai Yoshitaka、Mochizuki Hideki、Baba Kousuke
    • Journal Title

      Movement Disorders

      Volume: 35 Issue: 2 Pages: 256-267

    • DOI

      10.1002/mds.27887

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease2018

    • Author(s)
      Uenaka Takeshi、Satake Wataru、Cha Pei-Chieng、Hayakawa Hideki、Baba Kousuke、Jiang Shiying、Kobayashi Kazuhiro、Kanagawa Motoi、Okada Yukinori、Mochizuki Hideki、Toda Tatsushi
    • Journal Title

      Human Molecular Genetics

      Volume: 27 Pages: 3974-3985

    • DOI

      10.1093/hmg/ddy279

    • NAID

      120006549191

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] パーキンソン病の動物モデル2017

    • Author(s)
      早川 英規
    • Journal Title

      オベリスク

      Volume: 42 Pages: 24-32

    • Related Report
      2017 Research-status Report
  • [Presentation] In vitroにおけるalpha-synuclein細胞外分泌機構の検討2019

    • Author(s)
      Hideki Hayakawa, Kousuke Baba, Chi-Jing Choong, Kensuke Ikenaka , Toshihide Takeuchi, Yoshitaka Nagai, Hideki Mochizuki
    • Organizer
      NEURO2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] I Intranigral inoculation of Parkinson's disease linked mutation G51D alpha-synuclein firbils induces Lewy-like pathology in mice2018

    • Author(s)
      Hideki Hayakawa
    • Organizer
      IAPRD2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 野生型及び変異α synuclein 凝集体の分子特性に関する in vitro 及び in vivo での比較検討2018

    • Author(s)
      早川 英規
    • Organizer
      第12回パーキンソン病・運動機能コングレス
    • Related Report
      2018 Research-status Report
  • [Presentation] In vitro assessment of extracelluler alpha-synuclein secration2017

    • Author(s)
      Hideki Hayakawa
    • Organizer
      World congress of neurology 2017
    • Related Report
      2017 Research-status Report
  • [Presentation] 培養細胞系におけるαsynuclein伝播、凝集モデルの確立2016

    • Author(s)
      早川英規
    • Organizer
      第10回パーキンソン病・運動障害疾患コングレス
    • Place of Presentation
      京都ホテルオークラ
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Presentation] Establishment of in vitro model to elucidate mechanism u nderlying propagation of alpha-synuclein2016

    • Author(s)
      早川英規
    • Organizer
      第57回日本神経学会学術大会
    • Place of Presentation
      神戸コンベンションセンター
    • Year and Date
      2016-05-18
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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