Elucidation of the mechanism of LRRK2 activation induced by lysosomal stress and its application to drug development

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07816
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• 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), 講師 (10533903)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: LRRK2 / リソソーム / Rab / リン酸化 / パーキンソン病 / αシヌクレイン

Outline of Final Research Achievements

LRRK2 is a major causative protein for Parkinson’s disease (PD), and is a kinase that phosphorylates Rab GTPases such as Rab8 and Rab10 in cells. Since hyperactivation of LRRK2 has been implicated in PD, we sought to elucidate the regulatory mechanism of LRRK2 activation. In this study, we found that LRRK2 activity to phosphorylate Rab is enhanced by lysosomal stress loading to cells, that multiple regulatory factors including Rab29 are involved in the activation process, and that LRRK2 activation causes the extracellular release of alpha-synuclein, another PD-causative protein accumulated in PD brains.

Free Research Field

分子神経病理学

Academic Significance and Societal Importance of the Research Achievements

LRRK2の異常活性化の抑制はパーキンソン病の新規治療戦略として有望と考えられるが、本研究から、LRRK2活性化に関わる制御因子や経路が明らかになったことで、それらの因子も創薬標的になりうると考えられた。学術的には、LRRK2を中心とした新規のリソソームストレス応答機構とその制御メカニズムを見出したことで、細胞の恒常性維持機構に対する新たな理解が得られた。