Elevated FUS levels by overriding its autoregulation produce gain-of-toxicity properties that disrupt protein and RNA homeostasis

Ho, Ling (2019) Elevated FUS levels by overriding its autoregulation produce gain-of-toxicity properties that disrupt protein and RNA homeostasis Autophagy (IF: 13.3) 15(9) 1665-1667

Abstract

Coding or non-coding mutations in FUS (fused in sarcoma) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition to familial ALS, abnormal aggregates of FUS are present in a portion of FTD and other neurodegenerative diseases independent of their mutations. Broad expression within the central nervous system of either wild-type or two ALS-linked human FUS mutants produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated to maintain an optimal steady-state level. Increasing FUS expression by saturating its autoregulatory mechanism results in rapidly progressive neurological phenotypes and dose-dependent lethality. Genome-wide expression analysis reveals genetic mis-regulations distinct from those via FUS reduction. Among these are increased expression of lysosomal proteins, suggestive of disruption in protein homeostasis as a potential gain-of-toxicity mechanism. Indeed, increased expression of wild-type FUS or ALS-linked mutant forms of FUS inhibit macroautophagy/autophagy. Collectively, our results demonstrate that: (1) mice expressing FUS develop progressive motor deficits, (2) increased FUS expression by overriding its autoregulatory mechanism accelerates neurodegeneration, providing a basis for FUS involvement without mutation, and (3) disruption in both protein homeostasis and RNA processing contribute to FUS-mediated toxicity.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693452
http://www.ncbi.nlm.nih.gov/pubmed/31230528
http://dx.doi.org/10.1080/15548627.2019.1633162

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