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

Shuo Chien Ling, Somasish Ghosh Dastidar, Seiya Tokunaga, Wan Yun Ho, Kenneth Lim, Hristelina Ilieva, Philippe A. Parone, Sheue Houy Tyan, Tsemay M. Tse, Jer Cherng Chang, Oleksandr Platoshyn, Ngoc B. Bui, Anh Bui, Anne Vetto, Shuying Sun, Melissa McAlonis-Downes, Joo Seok Han, Debbie Swing, Katannya Kapeli, Gene W. YeoLino Tessarollo, Martin Marsala, Christopher E. Shaw, Greg Tucker-Kellogg, Albert R. La Spada, Clotilde Lagier-Tourenne, Sandrine Da Cruz, Don W. Cleveland

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere40811
JournaleLife
Volume8
DOIs
StatePublished - Feb 12 2019

Keywords

  • FUS
  • RNA metabolism
  • amyotrophic lateral sclerosis (ALS)
  • autophagy-lysosome
  • frontotemporal degeneration (FTD)
  • homeostasis
  • mouse
  • neuroscience

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis'. Together they form a unique fingerprint.

  • Cite this

    Ling, S. C., Dastidar, S. G., Tokunaga, S., Ho, W. Y., Lim, K., Ilieva, H., Parone, P. A., Tyan, S. H., Tse, T. M., Chang, J. C., Platoshyn, O., Bui, N. B., Bui, A., Vetto, A., Sun, S., McAlonis-Downes, M., Han, J. S., Swing, D., Kapeli, K., ... Cleveland, D. W. (2019). 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