ORCID Profile
0000-0001-6151-2964
Current Organisation
The University of Texas at Austin
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Publisher: eLife Sciences Publications, Ltd
Date: 12-02-2019
DOI: 10.7554/ELIFE.40811
Abstract: 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 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.
Publisher: American Geophysical Union (AGU)
Date: 11-2019
DOI: 10.1029/2019GC008637
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-08-2021
Abstract: AR isoform 2–encoded variant acts as a transcriptional modulator of AR genomic activity and is a target for therapy for SBMA.
Location: United States of America
No related grants have been discovered for Albert La Spada.