Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis

Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis

Blog Article

Mutations in coding rumchata proof and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS).The latter mutations may exert toxicity by increasing FUS accumulation.We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology.FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels.Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality.

Transcriptome analysis reveals mis-regulation of genes that are 15-eg1053cl largely not observed upon FUS reduction.Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism.Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.