Zeroing in on aberrant membrane trafficking in molecular pathogenesis of Parkinson's disease

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461263
• 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, 大学病院, 講師 (70361079)
• Co-Investigator(Renkei-kenkyūsha): Nagai Yoshitaka 大阪大学, 大学院医学系研究科, 教授 (60335354)
• Research Collaborator: Sugeno Naoto 東北大学, 大学病院, 助教 (30509550)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: パーキンソン病 / PARK17 / VPS35 / レトロマー / エンドソーム / カテプシンD / アルファシヌクレイン / ショウジョウバエモデル

Outline of Final Research Achievements

In this study, we first showed that the silencing of VPS35 in cultured cells caused a reduction in the distribution of CI-MPR and impaired the maturation of CTSD. Second, we found that the amount of pro-CTSD was substantially increased not only in the culture medium of the VPS35-deficient cells but also in the CSF from sporadic PD patients. Third, we demonstrated that silencing VPS35 impairs the maturation of CTSD, which occurs concomitant with a striking accumulation of αSYN in lysosomes. Finally, we showed that the RNAi-mediated silencing of dVPS35 not only induced the accumulation of the insoluble αSYN species in the brain but also exacerbated mild eye disorganization, as well as locomotor impairment in the flies expressing the human wt-αSYN. Cumulatively, these data suggest that the retromer-dependent sorting machinery plays a role in αSYN catabolism by modulating the intracellular processing and activation of CTSD and might thereby contribute to the pathogenesis of PD.

Free Research Field

病態医科学