期刊
MOLECULAR CELL
卷 80, 期 4, 页码 666-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.10.014
关键词
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资金
- NIH [1-F31-NS113439, 1-T32-GM007231-45, 1-RF1-NS113636-01, 1-R01-GM122569, 1R01-GM120353]
- National Science Foundation via the Center for Physics of Living Cells [PHY-1430124]
- Howard Hughes Medical Institute
- NSF Research Experience for Undergraduates
The RNA-binding protein fused in sarcoma (FUS) can form pathogenic inclusions in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Over 70 mutations in Fus are linked to ALS/FTLD. In patients, all Fus mutations are heterozygous, indicating that the mutant drives disease progression despite the presence of wild-type (WT) FUS. Here, we demonstrate that ALS/ FTLD-linked FUS mutations in glycine (G) strikingly drive formation of droplets that do not readily interact withWT FUS, whereas arginine (R) mutants form mixed condensates withWT FUS. Remarkably, interactions between WT and G mutants are disfavored at the earliest stages of FUS nucleation. In contrast, R mutants physically interact with the WT FUS such that WT FUS recovers the mutant defects by reducing droplet size and increasing dynamic interactions with RNA. This result suggests disparate molecular mechanisms underlying ALS/FTLD pathogenesis and differing recovery potential depending on the type of mutation.
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