Investigating the factors regulating FUS phase transition

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15190
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Okayama University
• Principal Investigator: Morihara Ryuta 岡山大学, 大学病院, 講師 (40895257)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: fused in sarcoma / 液－液相分離 / 前頭側頭型認知症 / 筋萎縮性側索硬化症 / アルギニンメチル化

Outline of Final Research Achievements

When physiological phase separation of FUS is disrupted, FUS abnormally aggregates to form inclusion bodies. In this study, we focused on arginine methylation of FUS as one of the factors regulating FUS phase separation, and performed mass spectrometry on brain samples from four groups: familial ALS with FUS mutation (ALS-FUS), FTLD with FUS accumulation (FTLD-FUS), sporadic ALS, and normal controls. The results showed that arginine residues tended to be demethylated in FTLD-FUS compared to normal controls, and that specific arginine residues were significantly demethylated, suggesting that demethylation of these specific arginine residues may cause increased phase separation of FUS. This suggests that demethylation of these specific arginine residues may be responsible for the increased phase separation of FUS.

Free Research Field

認知症

Academic Significance and Societal Importance of the Research Achievements

RNA結合蛋白の一種であるFUSは、相分離という現象によって可逆的に「分散状」「滴状」「ゲル状」に形態を変化させるが、相分離が破綻すると異常凝集して神経障害を引き起こす。本研究はこの異常凝集の原因として、FUSの特定のアルギニン残基の脱メチル化が関係することを明らかにした。FUS凝集が原因となる筋萎縮性側索硬化症及び前頭側頭型認知症の病因解明と治療法開発に向けての端緒になる可能性がある。