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

2018 Fiscal Year Final Research Report

• 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
• Keywords: LRRK2 / リソソーム / Rab / リン酸化 / パーキンソン病

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.

Free Research Field

分子神経病理学

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。