Functional-structural relationship of liquid-liquid phase separation caused by ALS-causing proteins and its pathological significance.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03593
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Kanekura Kohsuke 東京医科大学, 医学部, 准教授 (10508568)
• Co-Investigator(Kenkyū-buntansha): 早水 裕平 東京工業大学, 物質理工学院, 准教授 (80443216)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 液液相分離 / 筋萎縮性側索硬化症 / C9ORF72 / TDP-43

Outline of Final Research Achievements

ALS-related proteins such as C9ORF72 dipeptide repeat proteins and TDP-43 are thought to contribute to ALS pathogenesis by disturbing phase separation homeostasis, but their molecular mechanisms have remained unclear. In this study, we analyzed why C9ORF72-derived poly(PR) is toxic by combining various structural variants, multi-omics analyses, and in silico analysis, and found that although the insertion of Pro between Arg is disadvantageous in terms of binding energy, it promotes multivalent binding and enhanced phase separation, resulting in toxicity.

Free Research Field

神経内科学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、C9ORF72由来ジペプチドの機能構造連関が初めて明らかとなった。本研究を応用することで、C9ORF72-poly(PR)の毒性機構を理解し、さらに相分離異常を標的とした新規治療法の開発にもつながる可能性がある。また、本研究は非膜性オルガネラの形成機構など広く科学分野へ寄与する可能性がある。研究生はは論文の出版や学会発表を通じて学術界で知見を共有し、さらに一般社会へ還元される。