GSE125125

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Summary

Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We showhere that broad expression within the nervous system of wild type or either of two ALS-linkedmutants of human FUS produces progressive motor phenotypes accompanied bycharacteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in whichwild type or ALS-linked mutants of human FUS downregulating endogenous FUS at bothmRNA and protein levels. Increasing wild type human FUS expression achieved bysaturating this autoregulatory mechanism produces a rapidly progressive neurologicalphenotype and dose-dependent lethality. Genome-wide expression analysis reveals mis-regulation of genes that are largely distinct from the alterations observed by the acute FUS reduction in the spinal cord. Among these are increased expression of lysosomal proteins,suggestive of disruption in protein homeostasis as a potential gain-of-toxic mechanism.Indeed, increased expression of wild type and ALS-linked mutations in FUS inhibitautophagy with accumulated p62/sequestosome observed in spinal cord motor neurons.Taken together, our data suggests that overriding FUS autoregulation triggers gain-of-toxicproperties in the autophagy-lysosome axis and deregulation of RNA metabolism, highlightinga disruption in protein and RNA homeostasis in FUS-mediated toxicity.