Exploring Novel Mechanisms of Lysosome Distribution for Parkinson's Disease Therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Sasazawa Yukiko 順天堂大学, 大学院医学研究科, 准教授 (20594922)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: パーキンソン病 / リソソーム / トラフィッキング / オートファジー / 酸化ストレス

Outline of Final Research Achievements

Parkinson's disease (PD) is a progressive neurodegenerative disorder with an increasing number of patients each year. Our metabolomic analysis using serum from PD patients revealed alterations in polyamine metabolism and elevated levels of the toxic substance acrolein. Analysis of the cellular response to acrolein identified a novel mechanism in which lysosomes accumulate at the microtubule-organizing center (MTOC) and autophagy is induced via phosphorylated JIP4. Furthermore, this response was found to be a cellular defense mechanism against oxidative stress. Additionally, screening for compounds that induce lysosome accumulation without toxicity identified albendazole, which promotes autophagy with lysosome accumulation and degrades the PD-associated protein alpha-synuclein.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究はリソソーム分布を調節する新規メカニズムを提示し、JIP4の新しい役割を明らかにしたという点で学術的意義は大きい。さらに、同定した薬剤はリソソーム分布を変化させるというこれまでにない新しいタイプのオートファジー促進薬であり、根本的治療薬のないパーキンソン病治療薬へ応用が期待できる。