Regulatory mechanism of lysosomal homeostasis by LRRK2 and its relevance to Parkinson's disease

• Project/Area Number: 16K07039
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: The University of Tokyo
• Principal Investigator: Kuwahara Tomoki 東京大学, 大学院医学系研究科(医学部), 特任助教 (10533903)
• Research Collaborator: IWATSUBO Takeshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); 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); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: LRRK2 / リソソーム / Rab / リン酸化 / パーキンソン病 / Rabタンパク質 / オートファジー / 神経変性疾患

Outline of Final Research Achievements

Parkinson's disease-related protein LRRK2 is a kinase that phosphorylates Rab family small G proteins, and has been implicated in the regulation of lysosome morphology. In this study, we investigated the role of LRRK2 and its substrate Rab especially on lysosomal regulation, and found that LRRK2-mediated phosphorylation of Rab8 and Rab10 plays an important role in a novel lysosomal stress-responsive pathway. We additionally found that LRRK2-mediated phosphorylation of Rab7L1 regulates the morphology of Golgi apparatus. Our data support the notion that Parkinson-linked mutations in LRRK2 may abnormally enhance these regulatory pathways in cells.

Academic Significance and Societal Importance of the Research Achievements

LRRK2の生理的基質として近年になりRabが同定され、その役割が注目されていたが、我々は世界に先駆けてリソソームの恒常性維持に働くことを明らかにした。また、細胞内輸送の重要な制御因子であるRabがストレス依存的なリン酸化により新たな機能を獲得することを示した点で、学術的意義も大きい。LRRK2はパーキンソン病発症の鍵となる分子と考えられ、その詳細な機能の解明により、疾患発症機構の理解および治療薬開発にもつながるものと期待される。

Research Products

• [Int'l Joint Research] コロンビア大学(米国)
• [Journal Article] LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology. (2018)
  • Author(s): Fujimoto T, Kuwahara T, Eguchi T, Sakurai M, Komori T, Iwatsubo T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 2 Pages: 17081715-17081715
  • DOI: 10.1016/j.bbrc.2017.12.024
  • Peer Reviewed
• [Journal Article] LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts. (2016)
  • Author(s): Kuwahara T, Inoue K, D'Agati VD, Fujimoto T, Eguchi T, Saha S, Wolozin B, Iwatsubo T, Abeliovich A.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1
  • DOI: 10.1038/srep29945
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Maintenance of lysosomal homeostasis by LRRK2 and its substrate Rab GTPases (2019)
  • Author(s): Tomoki Kuwahara, Tomoya Eguchi, Maria Sakurai, Takeshi Iwatsubo
  • Organizer: The 14th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2019)
  • Int'l Joint Research
• [Presentation] Maintenance of lysosomal homeostasis by LRRK2 and Rab GTPases: Implications for the pathomechanism of Parkinson’s disease (2019)
  • Author(s): Tomoki Kuwahara, Tomoya Eguchi, Maria Sakurai, Tadayuki Komori, Kai Funakawa, Takeshi Iwatsubo
  • Organizer: 5th World Parkinson Congress
  • Int'l Joint Research
• [Presentation] LRRK2と基質Rabによるリソソームストレス制御のメカニズム (2019)
  • Author(s): 桑原知樹、江口智也、櫻井まりあ、小森禎之、舟川開、岩坪威
  • Organizer: 第92回日本生化学会大会
• [Presentation] Rab7L1によるLRRK2の活性化と細胞内局在化機構の解析 (2018)
  • Author(s): 桑原知樹、小森禎之、藤本哲太、江口智也、櫻井まりあ、岩坪威
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] LRRK2と基質Rab GTPaseによるリソソーム恒常性維持機構の解析 (2018)
  • Author(s): 櫻井まりあ、江口智也、桑原知樹、岩坪威
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Maintenance of lysosomal homeostasis by Parkinson-linked LRRK2 and Rab GTPases (2018)
  • Author(s): Tomoya Eguchi, Tomoki Kuwahara, Maria Sakurai, Genta Ito, Takeshi Iwatsubo
  • Organizer: UK-Japan Neuroscience Symposium
  • Int'l Joint Research / Invited
• [Presentation] Analyses of molecular and functional relationship between LRRK2 and RAB7L1 (2017)
  • Author(s): Tomoki Kuwahara, Tetta Fujimoto, Tomoya Eguchi, Maria Sakurai, Tadayuki Komori, Takeshi Iwatsubo
  • Organizer: The 13th international conference on Alzheimer's and Parkinson's diseases
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-03-29
  • Int'l Joint Research
• [Presentation] パーキンソン病病因遺伝子産物LRRK2がRab7L1リン酸化に果たす役割 (2017)
  • Author(s): 藤本哲太、桑原知樹、岩坪威
  • Organizer: 2017年度生命科学系学会合同年次大会 (ConBio2017)
• [Presentation] パーキンソン病病因遺伝子産物LRRK2のリソソーム恒常性維持における役割 (2017)
  • Author(s): 江口智也、桑原知樹、櫻井まりあ、伊藤弦太、岩坪威
  • Organizer: 2017年度生命科学系学会合同年次大会 (ConBio2017)
• [Presentation] The dynamic changes in the localization of LRRK2 in macrophage cells (2016)
  • Author(s): Tomoya Eguchi, Tomoki Kuwahara, Genta Ito, Takeshi Iwatsubo
  • Organizer: Society for Neuroscience 2016 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] The relationship between LRRK2 and Rab GTPase family (2016)
  • Author(s): Tetta Fujimoto, Tomoki Kuwahara, Tadayuki Komori, Takeshi Iwatsubo
  • Organizer: Society for Neuroscience 2016 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Remarks] 東京大学大学院医学系研究科神経病理学分野ホームページ
  • URL: http://www.neuropathology.m.u-tokyo.ac.jp/