Analysis of physicochemical features of the amyloid-nuclei forming alpha-synuclein from fibril formation kinetics

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15245
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Ohgita Takashi 京都薬科大学, 薬学部, 助教 (80737263)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: αシヌクレイン / アミロイド線維 / 凝集核 / パーキンソン病 / シヌクレイノパチー

Outline of Final Research Achievements

In this study, the structural feature of amyloid-nuclei of alpha-synuclein (aS), a Parkinson's disease-related intraneuronal protein, was estimated from its fibril formation kinetics. The significant results are 1) unraveling the mechanism of accelerated nucleation of aS by the Parkinson's disease-related N-terminal mutations and the C-terminal truncations, 2) identification of the role of S87 residue of aS as the hotspot residue for regulating fibril formation, and 3) elucidating the correlation between protein hydrophobicity and the amounts of nuclei formed during lag phase. These findings advance the understanding of the nucleation mechanism of aS and provide clues for developing nucleation inhibitors for Parkinson's disease therapy.

Free Research Field

生物物理化学

Academic Significance and Societal Importance of the Research Achievements

αシヌクレイン凝集核はパーキンソン病の主要病原因子であるが、不安定な構造体であるために物性解析が難しく、これを標的とした治療分子は設計できていない。本研究で得られたαシヌクレインの凝集核形成メカニズムに関する知見は、凝集核の形成を制御する分子の設計基盤となりうる情報であり、凝集核形成阻害を機序とするパーキンソン病根治薬の開発に貢献する。