Phase-separation dynamics of pathogenic RNA granules revealed by visualization and manipulation method of endogenous RNA

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06745
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: The University of Tokyo (2023); Institute of Physical and Chemical Research (2021)
• Principal Investigator: Takai Akira 東京大学, 大学院医学系研究科(医学部), 助教 (60637205)
• Co-Investigator(Kenkyū-buntansha): 池田 一穂 東京大学, 大学院医学系研究科(医学部), 講師 (20642565)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNA / ライブイメージング / 液－液相分離

Outline of Final Research Achievements

The formation of RNA granules is regulated by liquid-liquid phase separation, and is known to be involved in tumorigenesis and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Especially in neurodegenerative disorders, it has been reported that RNA granules undergo a phase transition from liquid phase to gel phase due to mutations in RNA granule component proteins, leading to cytotoxicity. On the other hand, it is still unclear how RNA itself is involved in the phase separation dynamics of RNA granules and cytotoxicity. In this study, I developed a novel method for visualization and manipulation of pathogenic RNA to clarify the phase separation dynamics of RNA granules from the RNA level, and elucidated some of the physiological functions of RNA granule dynamics in living cells.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

これまでは技術的な限界のため、RNA顆粒の液-液相分離動態の解析はRNA顆粒構成タンパク質側からのアプローチがほとんどであった。一方で2017年NatureでのJainとValeの報告により、非翻訳領域のRNA反復配列そのものが病原性のRNA顆粒形成を担うという説が提唱され、既存法ではアプローチ困難なRNA顆粒の特性が明らかになってきた。本申請研究ではこの課題にRNA側からアプローチする新たな解析法を提唱し、病原性のRNA顆粒におけるRNAそのものの病理学的意義の一端を明らかにした。今後はこのRNAそのものの病理学的意義を指標に、新たな疾患治療法の開発や創薬に繋がることが期待される。