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Pathogenesis of ALS linked p62-mutants from the point of view of autophagy and oxidative stress

Research Project

Project/Area Number 18K07505
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Watanabe Yoshihisa  京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)

Co-Investigator(Kenkyū-buntansha) 徳田 隆彦  京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords筋委縮性硬化症 / 前頭側頭型認知症 / p62 / オートファジー / 酸化ストレス / 神経変性疾患 / 筋萎縮性側索硬化症 / 酸化ストレス応答 / ALS / 変異 / SQSTM1/p62
Outline of Final Research Achievements

Mutations in a multifunctional adaptor protein p62 are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). p62 is implicated in selective autophagy and oxidative stress response. To investigate the pathogenic mechanism of ALS/FTD by p62 mutations, we produced the stable cell lines expressing p62-WT, P392L and G425R. Interestingly, both p62 mutants were cleaved at specific positions under stress conditions. Next, we assessed oxidative stress response via the p62-Keap1-Nrf2 axis in p62 mutant cells. Heme oxygenase-1 expression was significantly suppressed in both p62 mutant cells. Furthermore, p62 mutations decreased the binding of the UBA domain to ubiquitinated proteins. These results suggest that reduction of stress response and autophagic clearance of ubiquitinated proteins might be involved in the pathogenic mechanism of ALS/FTD by p62 mutations.

Academic Significance and Societal Importance of the Research Achievements

本研究では筋委縮性側索硬化症(ALS)/前頭側頭型認知症(FTD)の原因遺伝子の1つであるp62による疾患発症機序の研究を行った。ALS/FTD変異p62はストレスにより異常な切断を受け、酸化ストレス応答やオートファジーに障害を及ぼすことが明らかになった。今後、この異常切断を行うプロテアーゼを解明することで新たな治療法の開発につながる可能性がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (15 results)

All 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (10 results) (of which Int'l Joint Research: 2 results) Book (1 results)

  • [Journal Article] Ubiquitin, Autophagy and Neurodegenerative Diseases2020

    • Author(s)
      Watanabe Y, Taguchi K, Tanaka M.
    • Journal Title

      Cells

      Volume: 9 Issue: 9 Pages: 2022-2022

    • DOI

      10.3390/cells9092022

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] α-Synuclein Promotes Maturation of Immature Juxtaglomerular Neurons in the Mouse Olfactory Bulb.2020

    • Author(s)
      Taguchi K., Watanabe Y., Tsujimura A., and Tanaka M.
    • Journal Title

      Molecular Neurobiology

      Volume: 57 Issue: 3 Pages: 1291-1304

    • DOI

      10.1007/s12035-019-01814-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Expression of α-synuclein is regulated in a neuronal cell type-dependent manner.2019

    • Author(s)
      田口勝敏、渡邊義久、辻村敦、田中雅樹
    • Journal Title

      Anatomical Science International

      Volume: 94 Issue: 1 Pages: 11-22

    • DOI

      10.1007/s12565-018-0464-8

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppression of autophagic activity by Rubicon is a signature of aging.2019

    • Author(s)
      Nakamura S, Oba M, Suzuki M, Takahashi A, Yamamuro T, Fujiwara M, Ikenaka K, Minami S, Tabata N, Yamamoto K, Kubo S, Tokumura A, Akamatsu K, Miyazaki Y, Kawabata T, Hamasaki M, Fukui K, Sango K, Watanabe Y, Takabatake Y, Kitajima T, Okada Y, Mochizuki H, Isaka Y, Antebi A, Yoshimori T.
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 847-847

    • DOI

      10.1038/s41467-019-08729-6

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 嗅球傍糸球体神経に高発現するパーキンソン病責任分子α-シヌクレインの機能解析2020

    • Author(s)
      田口勝敏、渡邊義久、辻村敦、田中雅樹.
    • Organizer
      Neuro2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] ALS-FTD-linked mutations of SQSTM1/p62 suppress oxidative stress response via the NRF2-Keap1 axis2020

    • Author(s)
      Watanabe Y, Taguchi K, Tsujimura A, Ueyama M, Nagai Y, Tanaka M.
    • Organizer
      FENS2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 一過性脳虚血モデルを用いた嗅球傍糸球体細胞に高発現するパーキンソン病関連分子α-シヌクレインの機能解析2020

    • Author(s)
      田口勝敏, 渡邊義久, 辻村敦, 田中雅樹
    • Organizer
      第125回日本解剖学会総会・全国学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] α-Synuclein promotes maturation of immature juxtaglomerular neurons in the mouse olfactory bulb2019

    • Author(s)
      Taguchi, K., Watanabe, Y., Tsujimura, A., Tanaka, M
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 虚血モデルを用いた嗅球傍糸体細胞に高発現するパーキンソン病関連分子α―シヌクレインの機能解析2019

    • Author(s)
      田口勝敏、渡邊義久、辻村敦、田中雅樹
    • Organizer
      第60回日本組織細胞化学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脳虚血モデルを用いた嗅球傍糸球体細胞に高発現するパーキンソン病関連分子α-シヌクレインの機能解析2019

    • Author(s)
      田口勝敏, 渡邊義久, 辻村敦, 田中雅樹
    • Organizer
      第9回4大学連携研究フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] 脳虚血モデルを用いた嗅球傍糸球体細胞に高発現するα-シヌクレインの機能解析2019

    • Author(s)
      田口勝敏、渡邊義久、辻村敦、田中雅樹
    • Organizer
      第124回日本解剖学会総会・全国学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] α-Sunuclein counteracts immature identity of the periglomerular cells in the mouse olfactory bulb after ischemic stroke.2018

    • Author(s)
      K. Taguchi, Y. Watanabe, A. Tsujimura, M. Tanaka.
    • Organizer
      第41回日本神経科学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Isolation and characterization of cell-to-cell transmissible α-synuclein seeds2018

    • Author(s)
      Taguchi K, Watanabe Y, Tsujimura A, Tanaka M.
    • Organizer
      8th APICA
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 神経細胞間伝播性α-シヌクレインシードの同定とその解析2018

    • Author(s)
      田口勝敏、渡邊義久、辻村敦、田中雅樹
    • Organizer
      第94回日本解剖学会近畿支部学術集会
    • Related Report
      2018 Research-status Report
  • [Book] Regulation of Autophagy by the Heat Shock Factor 1-Mediated Stress Response Pathway. In: Asea A., Kaur P. (eds) Heat Shock Proteins and Stress. Heat Shock Proteins, vol 15.2018

    • Author(s)
      Watanabe Y., Tanaka M.
    • Total Pages
      315
    • Publisher
      Springer Publishing
    • ISBN
      9783319907246
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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