Liquid-solid phase equilibrium of neuronal RNA granules involved in cognitive function and neurodegenerative diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03161
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Center for Novel Science Initatives, National Institutes of Natural Sciences
• Principal Investigator: Shiina Nobuyuki 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 准教授 (30332175)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: RNA顆粒 / 液-液相分離 / mRNA / 局所的翻訳 / 神経変性疾患 / TDP-43 / FUS / RNG105

Outline of Final Research Achievements

TDP-43 and FUS, which are the causative gene products of neurodegenerative diseases, are thought to cause diseases by accumulating and aggregating in RNA granules in neurons. In this study, we found that the accumulation of TDP-43 and FUS in RNA granules increased the fluidity of an RNA granule scaffold protein RNG105 in the granules, causing RNG105 to dissociate from the granules into the cytoplasm. Simultaneously, the amount of mRNA uptake into the granules was reduced, and the local translation in the granules was also reduced. These results provide a new model that dissociation of RNG105 from RNA granules by TDP-43 and FUS, and concomitant dissociation of mRNA and the reduced local translation within the granules, are the basis of the pathology of neurodegenerative diseases.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

RNA顆粒は、RNA結合タンパク質とmRNAの液-液相分離によって形成され、シナプスへのmRNA輸送と局所的翻訳の制御を介してシナプス長期増強及び長期記憶に必須の役割を担う。このことから、TDP-43及びFUSの凝集化によるRNA顆粒の機能不全が、シナプス形成不全や認知症を伴う神経変性疾患の病態基盤になると考えられており、そのメカニズム解明は喫緊の課題である。本研究は、RNA顆粒形成因子のほとんどがTDP-43及びFUSの影響を受けない反面、RNG105が特異的に顕著な影響を受け、同時にRNA顆粒の機能が低下することを見出した。この成果は神経変性疾患の新たな病態メカニズムを提案するものである。