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

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.

KEYWORDS:

• Amyotrophic lateral sclerosis (ALS)
• autophagy
• frontotemporal dementia (FTD)
• FUS
• lysosome
• p62
• SQSTM1/p62

Acknowledgments

We thank Daniel Klionsky and Eddy Leman for editing the manuscript. This work was supported in part by grants to S.-C. L. from the National Medical Research Council (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/2017) and Ministry of Education (MOE2016-T2-1-024), Singapore.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Ministry of Education, Singapore [MOE2016-T2-1-024]; National Medical Research Council, Singapore [NMRC/OFIRG/0042/2017]; National Medical Research Council, Singapore [NMRC/OFIRG/0001/2016].