Analysis of altered RNA behavior induced by neurodegeneration-associated cytoplasmic protein aggregation.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16259
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Hiroshima University
• Principal Investigator: Yasuda Kyota 広島大学, 統合生命科学研究科(理), 助教 (40816344)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ALS / FUS / RNA localization / Translation regulation / VCP / MAP7 / LLPS

Outline of Final Research Achievements

The cytoplasmic protein aggregation found in amyotrophic lateral sclerosis (ALS) is still unclear in its relationship to pathogenesis. This study targeted FUS, one of the proteins undergoes ALS-associated cytoplasmic aggregation. Previous studies have shown that FUS aggregation promotes abnormal activation of RNA translation within the FUS aggregates. In this study, we mainly searched for factors that cause ectopic translation and analyzed their functions relating to ectopic translation. The main finding is involvement of VCP in FUS aggregation and ectopic translation. In brief, ALS-related mutation to FUS reduce the interaction between VCP protein and FUS protein. This reduction of VCP-FUS interaction disrupts the regulation of FUS aggregation by VCP. VCP regulates FUS phase separation through consuming ATP around FUS. We also found that the ectopic translation was alleviated by VCP overexpression.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ALSは進行性の神経変性疾患の１つであり、最終的に呼吸筋麻痺に至る重篤な症状を示す。現在も多くの研究が病態解明を目指しているが、根本的な治療法は確立されていない。本研究では、ALS発症メカニズム解明を目的とし、ALSの病理的特徴であるFUSタンパク質凝集がRNAの翻訳制御異常を引き起こす仕組みに着目した。結果、VCPタンパク質によるFUS相分離制御機構が存在し、ALS関連変異がこれを阻害することを見出した。VCPの過剰発現が凝集による異常な翻訳活性化を緩和することを示唆するデータも得た。これらの成果は、細胞内でのFUS相分離制御機構を新たに提唱するとともに、ALS治療法確立にも一石を投じる。