Analysis of the molecular mechanism by which mitochondrial dysfunction leads to alpha-Synaclein aggregation

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15465
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Meng Hongrui 順天堂大学, 医学(系)研究科(研究院), 特任助教 (90736498)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: パーキンソン病 / α-synuclein / ミトコンドリア / CHCHD2

Outline of Final Research Achievements

Parkinson’s disease (PD) is characterized by the accumulation of aggregated α-synuclein into intraneuronal Lewy bodies (LBs). Mitochondrial dysfunction has been strongly implicated in the pathogenesis of PD. Our studies have shown that the missense mutation, T61I, in the familial PD-associated mitochondrial protein CHCHD2 causes mitochondrial dysfunction, exacerbating misfolded α-synuclein aggregation and LB formation. Using Drosophila harboring CHCHD2 T61I mutation and dopaminergic neuron cultures prepared from a PD patient with CHCHD2 T61I, we investigated the mechanism underlying the mitochondrial dysfunction-induced α-synuclein aggregation. Our in vivo and in vitro models characterized here will contribute to the understanding of the mechanism whereby mitochondrial dysfunction could be a risk factor for α-synuclein aggregation in the pathogenesis of PD.

Free Research Field

神経内科学関連

Academic Significance and Societal Importance of the Research Achievements

CHCHD2変異によりα-synucleinが顕著に凝集・蓄積することが、病理解析で明らかとなった。患者由来のiPS細胞とミトコンドリア変性を再現するモデルハエを作製し、ミトコンドリア異常がα-synucleinの凝集化を導く現象を再現できた。今後、ミトコンドリアの機能異常がいかにα-synucleinの凝集化を導くか、その分子機序を解明することにより、予防的、治療的対策が可能になると期待される。老人性神経変性疾患に関しては、不溶性タンパク質の蓄積を削減に未然に防ぐことが最も効果的かつ経済的な対処法と考えられ、本研究で解析したモデル動物はその開発に貢献する。