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

Author:

Ling, Shuo-Chien [ORCID]

Dastidar, Somasish Ghosh

Tokunaga, Seiya

Ho, Wan Yun

Lim, Kenneth

Ilieva, Hristelina

Parone, Philippe A

Tyan, Sheue-Houy

Tse, Tsemay M

Chang, Jer-Cherng

Platoshyn, Oleksandr

Bui, Ngoc B

Bui, Anh

Vetto, Anne

Sun, Shuying

McAlonis-Downes, Melissa

Han, Joo Seok

Swing, Debbie

Kapeli, Katannya

Yeo, Gene W

Tessarollo, Lino [ORCID]

Marsala, Martin

Shaw, Christopher E

Tucker-Kellogg, Greg

La Spada, Albert R [ORCID]

Lagier-Tourenne, Clotilde

Da Cruz, Sandrine

Cleveland, Don W
Author Address

Department of Physiology, National University of Singapore, Singapore, Singapore., Neurology, Duke University, Durham, United States., Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States., Department of Medicine, National University of Singapore, Singapore, Singapore., Department of Anesthesiology, University of California, San Diego, La Jolla, United States., Mouse Cancer Genetics Program, National Cancer Institute, Frederick, United States., Department of Cellular and Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, United States., Institute of Psychiatry, King 39;s College London, London, United Kingdom., Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States.,

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.

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Author Address