Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis
- National University of Singapore, Singapore
- Duke University, United States
- University of California, San Diego, United States
- National Cancer Institute, United States
- King's College London, United Kingdom
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.
Data availability
RNA-seq data have been deposited in NCBI's Gene Expression Omnibus with the GEO series accession number GSE125125.
Article and author information
Author details
Funding
National Medical Research Council (NMRC/OFIRG/0001/2016)
- Shuo-Chien Ling
Ministry of Education - Singapore (MOE2016-T2-1-024)
- Shuo-Chien Ling
National Institutes of Health (R01 AG033082)
- Albert R La Spada
Wellcome
- Christopher E Shaw
National Institutes of Health (R01 NS041648)
- Albert R La Spada
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- J Paul Taylor, St Jude Children's Research Hospital, United States
Ethics
Animal experimentation: All studies were carried out under protocols approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (UCSD) and the National University of Singapore (NUS), and were in compliance with Association for Assessment of Laboratory Animal Care guidelines for animal use. All studies were performed in such a manner as to minimize group size and animal suffering. The approved NUS protocol numbers are BR17-0928 and R16-0954.
Version history
- Received: August 5, 2018
- Accepted: February 11, 2019
- Accepted Manuscript published: February 12, 2019 (version 1)
- Version of Record published: February 25, 2019 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis
eLife 8:e40811.
https://doi.org/10.7554/eLife.40811
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