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Elucidation of the molecular pathogenesis of Parkinson disease by uncovering the LRRK2-Rab pathway

Research Project

Project/Area Number 17K08265
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

Ito Genta  東京大学, 大学院薬学系研究科(薬学部), 特任講師 (10431892)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsLRRK2 / パーキンソン病 / キナーゼ / GTPase / Rab / リソソーム / リン酸化 / 小胞輸送 / LRRK2 / Rab
Outline of Final Research Achievements

Although LRRK2, a causative gene product for Parkinson disease, has been shown to phosphorylate Rab proteins, its functional significance remains unknown. In this study, we found that Rab10 changes its subcellular localization from endoplasmic reticulum to lysosome. Interestingly, we also found that lysosomes change the localization if cells overexpressing LRRK2 were treated with LRRK2 inhibitors.
Moreover, we systematically identified proximal proteins of Rab29, an activation factor for LRRK2. We also established a genome-wide screening system that enables us to screen genes involved in the regulation of Rab10 phosphorylation as well as lysosomal positioning by LRRK2.
Taken together, we propose the involvement of dysregulation of the LRRK2-Rab pathway in the pathogenesis of Parkinson disease.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病はアルツハイマー病に次いで頻度の高い神経変性疾患であるが、現在その根本治療法は存在しない。主として高齢者に発症することから、超高齢社会を迎えた本邦において、その発症機序に基づく治療法の開発は急務である。私たちは、その変異により遺伝性のパーキンソン病の原因となるLRRK2タンパク質がRab10タンパク質をリン酸化(リン酸を付与する)ことを発見したが、本研究ではそのリン酸化がリソソームと呼ばれる細胞内小器官の恒常性維持に関与する可能性を提示した。リソソームは細胞内の老廃物の分解や細胞外への放出などを担当する器官であり、その異常がパーキンソン病の原因となる可能性が考えられる。

Report

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

    (16 results)

All 2019 2018 2017 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis2018

    • Author(s)
      Eguchi Tomoya、Kuwahara Tomoki、Sakurai Maria、Komori Tadayuki、Fujimoto Tetta、Ito Genta、Yoshimura Shin-ichiro、Harada Akihiro、Fukuda Mitsunori、Koike Masato、Iwatsubo Takeshi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 39

    • DOI

      10.1073/pnas.1812196115

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Physiological and pathological functions of LRRK2: implications from substrate proteins2018

    • Author(s)
      Araki Miho、Ito Genta、Tomita Taisuke
    • Journal Title

      Neuronal Signaling

      Volume: 2 Issue: 4

    • DOI

      10.1042/ns20180005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils2018

    • Author(s)
      Ying Fan, Andrew J.M. Howden, Adil R. Sarhan, Pawel Lis, Genta Ito, Terina N. Martinez, Kathrin Brockmann, Thomas Gasser, Dario R. Alessi, Esther M. Sammler
    • Journal Title

      Biochemical Journal

      Volume: 475 Issue: 1 Pages: 23

    • DOI

      10.1042/bcj20170803

    • URL

      https://localhost/en/publications/8e328228-a4ef-4461-a2b5-da32c810f90a

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Rab10 phosphorylation detection by LRRK2 activity using SDS-PAGE with a phosphate-binding tag2017

    • Author(s)
      Genta Ito, Taisuke Tomita
    • Journal Title

      Journal of Visualized Experiments

      Volume: 2017 Issue: 130

    • DOI

      10.3791/56688

    • URL

      https://pure.teikyo.jp/en/publications/26d982ce-adbf-4482-9160-745898f022b1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Characterization of Rab phosphorylation by LRRK kinases.2019

    • Author(s)
      Genta Ito, Kyohei Ito, Miho Araki, Taisuke Tomita
    • Organizer
      World Parkinson Congress 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 層板小体の恒常性維持におけるLRRK2の役割2019

    • Author(s)
      伊藤弦太、荒木美保、高鳥翔、富田泰輔
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Proteomic analysis of lamellar bodies in Lrrk2 knockout mice2019

    • Author(s)
      Miho Araki, Sho Takatori, Genta Ito, Taisuke Tomita
    • Organizer
      Neuroscience 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of Rab phosphorylation by LRRK2 kinases2019

    • Author(s)
      Genta Ito, Kyohei Ito, Miho Araki, Taisuke Tomita
    • Organizer
      World Parkinson Congress 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Physiological role of LRRK2 in lamellar body homeostasis2018

    • Author(s)
      Miho Araki, Sho Takatori, Genta Ito, Taisuke Tomita
    • Organizer
      2018年度日本生化学会関東支部例会
    • Related Report
      2018 Research-status Report
  • [Presentation] Physiological role of LRRK2 in lamellar body homeostasis2018

    • Author(s)
      Miho Araki, Sho Takatori, Genta Ito, Taisuke Tomita
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Characterization of Rab phosphorylation by LRRK2 kinases2018

    • Author(s)
      Genta Ito, Miho Araki, Kyohei Ito, Taisuke Tomita
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Phos-tag SDS-PAGEを用いたRabリン酸化の解析2018

    • Author(s)
      Genta Ito
    • Organizer
      第69回日本電気泳動学会総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Phos-tag SDS-PAGEを用いたRabリン酸化の解析2018

    • Author(s)
      Genta Ito
    • Organizer
      第69回日本電気泳動学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Phos-tag analysis of Rab10 phosphorylation by LRRK22017

    • Author(s)
      Genta Ito
    • Organizer
      第39回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [Remarks] 東京大学大学院薬学系研究科機能病態学教室

    • URL

      http://www.f.u-tokyo.ac.jp/~neuropsc/tomita/

    • Related Report
      2019 Annual Research Report 2017 Research-status Report
  • [Patent(Industrial Property Rights)] 自閉症発症機構に関連する接着分子2019

    • Inventor(s)
      富田泰輔、伊藤弦太、高鳥翔、長友亮太、吉田文明
    • Industrial Property Rights Holder
      富田泰輔、伊藤弦太、高鳥翔、長友亮太、吉田文明
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Research-status Report
    • Overseas

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Published: 2017-04-28   Modified: 2021-02-19  

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