biostudies-literatureLing SCNIA NIH HHSMedical Research CouncilMinistry of Education - SingaporeNINDS NIH HHSNational Institutes of HealthNational Medical Research CouncilWellcome TrustNIH HHSe40811https://www.ebi.ac.uk/biostudies/studies/S-EPMC6389288biostudies-literatureUnknown8Mutations in coding 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 largely not observed upon FUS reduction. Likely mechanisms for FUSeLifeOverriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.PMC6389288MOE2016-T2-1-024R01 AG033082R01 NS027036MC_G1000733NMRC/OFIRG/0001/2016R01 NS100023R01 NS041648G0500289Kapeli KLagier-Tourenne CTessarollo LYeo GWParone PAHo WYDa Cruz SSun SLing SCMarsala MDastidar SGTokunaga SShaw CECleveland DWTse TMVetto ATyan SHLa Spada ARBui AMcAlonis-Downes MHan JSSwing DPlatoshyn OTucker-Kellogg GLim KIlieva HChang JCBui NBfalseOverriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.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 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 largely not observed upon FUS reduction. Likely mechanisms for FUS2019-01-01T00:00:00Z2019 Feb2026-05-04T08:03:05.829Z2019-06-06T23:24:08ZS-EPMC63892883074770910.7554/eLife.40811