Regulation of alpha-synuclein aggregation and propagation by RNA G-quadruplexes.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06579
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kumamoto University
• Principal Investigator: Yabuki Yasushi 熊本大学, 発生医学研究所, 准教授 (70756121)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNA グアニン四重鎖 / α-Synuclein / 液－液相分離 / ゾル－ゲル相転移 / 神経変性

Outline of Final Research Achievements

Neurodegenerative disorders with Lewy bodies are progressive brain amyloidosis caused by the aggregation and propagation of pathogenic α-synuclein (α-Syn). The mechanism underlying neurodegeneration by α-Syn aggregation is still unknown, and then there is currently no fundamental cure. We demonstrated that α-Syn binds specifically to RNA G-quadruplex (G4RNA), and that G4RNA promoted liquid-liquid phase separation (LLPS) and aggregate formation of α-Syn in vitro. We also identified endogenous G4RNAs that contribute to the induction of α-Syn aggregation in mouse neurons. We investigated effects of G4 ligands on aggregated α-Syn-induced neurodegeneration. Taken together, we revealed a part of the mechanism of α-Syn aggregation and neurodegeneration induced by G4RNA.

Free Research Field

神経薬理学、神経科学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

脳神経病態における G4RNA の挙動・役割は良く分かっておらず、本研究により、G4RNA の病態生理学的意義の一部が明らかとなった。また、超高齢化社会である本国において、レビー小体病は増加しており、新規治療法や予防医学の発展が急務である。本研究は G4 構造が新たな治療標的になる可能性を示唆しており、ドラッグ・リポジショニングによる臨床開発や創薬研究への発展ができる。