Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis

Author:

Wang Yixin1,Liu Liu2,Chen Hui1,Yang Yinxue3,Mu Chenchen1,Ren Haigang1,Liu Yanli3,Yu Liqiang4,Fang Qi4,Wang Guanghui15,Hao Zongbing1

Affiliation:

1. Soochow University Department of Pharmacology, Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, , Suzhou, Jiangsu 215123 , China

2. The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People’s Hospital Department of Pharmacy, , Changsha, Hunan 410005 , China

3. Soochow University Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, , Suzhou, Jiangsu 215123 , China

4. The First Affiliated Hospital of Soochow University Department of Neurology, , Suzhou, Jiangsu 215123 , China

5. Soochow University MOE Key Laboratory, , Suzhou, Jiangsu 215123 , China

Abstract

Abstract GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.

Funder

National Natural Science Foundation of China

Priority Academic Program Development of Jiangsu Higher Education Institutions

China Postdoctoral Science Foundation

Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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