Zeroing in on membrane trafficking: its implication for molecular pathogenesis and curative therapy of Parkinson's disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Hasegawa Takafumi 東北大学, 医学系研究科, 准教授 (70361079)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: パーキンソン病 / メンブレントラフィック / エンドソーム / αシヌクレイン / DNAJC13 / ドパミントランスポータ－ / flotillin-1 / プリオン様伝播

Outline of Final Research Achievements

We have started this year of research focusing on the following projects: (i) intracellular vesicular trafficking and alpha-synuclein (αS) accumulation and neurodegeneration, and (ii) cell-to-cell spreading of aS. In the first project, we have now investigated how mutat DNAJC13 could drive neurrodegeneration leading to PD. Through this study, the co-expression of mutant DNAJC13 and αS in cells resulted in accumulation of αS due to defective endosomal trafficking. Furthermore, we found that expressing mutant DNAJC3 with αS in fly brains enhanced the accumulation of insoluble αS, and resulted in a loss of dopaminergic neurons. These defects had a significant impact on the motor performance of flies. In another project, we are elucidating the mechanisms of αS propagation using cellular and animal models. Through these observations, we found that flotillin-1 co-assembled with extracellular αS on cell surface, and αS enters into cells by hijacking the endocytic trafficking of DAT.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病をはじめとする神経変性疾患の原因究明と治療は、高齢化が進む21世紀において全世界的な課題である。一方、これらの疾患の発症機序は完全には解明されておらず、治療は対症療法に限定されており、進行抑制・根本的治療法は存在しない。本研究により明らかにされた病態メカニズムや創薬シーズは、症状進行による社会的資産の毀損の回避を介して医療・福祉への貢献に繋がることが期待され、創薬産業へのインパクトも大きいと予想される。