Pathophysiological analysis of Parkinson's Disease using PARK17 patient-derived iPS cell

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07302
• 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: Jikei University School of Medicine
• Principal Investigator: Okano Hirotaka James 東京慈恵会医科大学, 医学部, 教授 (90338020)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: パーキンソン病 / VPS35 / レトロマー / 新規オートファジー / Rab9

Outline of Final Research Achievements

We isolated iPSCs from two PD patients carrying the VPS35 D620N mutant. We revealed that the number of autophagic vacuoles was significantly decreased in ATG5-knockout fibroblast or ATG5-knockdown iPSCs-derived dopaminergic neurons compared with control cells. Furthermore, estrogen, which activates alternative autophagy pathways, increased the number of autophagic vacuoles in ATG5-knockdown VPS35 D620N mutant dopaminergic neurons. Estrogen induces Rab9 phosphorylation, mediated through Ulk1 phosphorylation, ultimately regulating alternative autophagy. Moreover, estrogen reduced the apoptosis rate of VPS35 D620N neurons, and this effect of estrogen was diminished under alternative autophagy knockdown conditions. In conclusion, Alternative autophagy might be important for maintaining neuronal homeostasis and may be associated with the neuroprotective effect of estrogen in PD with VPS35 D620N.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

これまで、古典的オートファジーを標的としたパーキンソン病治療が試みられてきたが、本研究結果から新規オートファジーの重要性も明らかになったため、今後の治療薬開発の幅が広がることが期待される。しかし、古典的オートファジーと比較すると新規オートファジーに関与するタンパク質群や分解される基質、両者のオートファジー機序の細胞内での役割の違いなどについて未解明な部分が多く、今後の研究の発展のためには新規オートファジー自体の研究発展が欠かせない。