Cell biological analysis of VPS35 mutation using iPSCs

2023 Fiscal Year Final Research Report

• Project/Area Number: 18K15468
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Bono Keiko 東京慈恵会医科大学, 医学部, 助教 (20753320)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: パーキンソン病 / iPS細胞 / エンドソーム / VPS35 / レトロマー

Outline of Final Research Achievements

Mutations in the Vacuolar protein sorting 35 (VPS35) gene have been linked to familial Parkinson’s disease (PD),PARK17. VPS35 is a key component of the retromer complex, which plays a central role in endosomal trafficking. We analyzed human induced pluripotent stem cell (iPSC)-derived neurons from PD patients with the VPS35 D620N mutation and addressed relevant disease mechanisms. In the disease group, dopaminergic (DA) neurons underwent extensive apoptotic cell death. The movement of Rab5a- or Rab7a-positive endosomes was slower, and the endosome fission and fusion frequencies were lower in the PD group than in the healthy control group. Furthermore, we found α-synuclein accumulation in TH positive DA neurons. Our results demonstrate the induction of cell death, endosomal dysfunction and α -synuclein accumulation in neural cells of the PD group.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

本研究結果によりVPS35 D620N変異はエンドソーム機能障害を引き起こし、α-シヌクレイン蓄積、ドパミンニューロン細胞死といったパーキンソン病にみられる病理所見を反映していることが明らかになり、VPS35が構成するタンパク複合体であるレトロマーはパーキンソン病の治療標的となり得ることが示された。