Molecular mechanisms and therapeutic strategies of Parkinson's disease through lysosomal function

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16998
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tohoku University
• Principal Investigator: Yoshida Shun 東北大学, 医学系研究科, 大学院非常勤講師 (60822905)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: レトロマー

Outline of Final Research Achievements

In Parkinson's disease, lysosomal function is controlled by various intracellular vesicle trafficking. In this study, we focused on the retromer, which has been shown to be related to lysosomal function in Parkinson's disease. First, we observed impaired retromer transport in cells overexpressing the Parkinson's disease-associated mutant DNAJC13. Furthermore, we found that DNAJC13 acts as a chaperone for SNX1, which is involved in retromer transport, triggered by clathrin. In rotenone-exposed cells, which are widely used as a model of Parkinson's disease, we confirmed that DNAJC13 inhibits the chaperone function of SNX1 and induces retromer impaiment.

Free Research Field

神経内科学分野

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病において変異型DNACJ13がレトロマー障害を引き起こすと共に、パーキンソン病モデル細胞として広く使用されるロテノン暴露細胞や、パーキンソン病における主要分子であるαシヌクレイン過剰発現でもレトロマー障害が引き起こされたという事実はパーキンソン病におけるレトロマー機能の重要性を示唆する結果であり、学術的意義があると考えられる。また、これを標的とした治療開発にもつながる結果と考えられ、社会的意義もあると考えられる。