Elevated FUS levels by overriding its autoregulation produce gain-of-toxicity properties that disrupt protein and RNA homeostasis - PubMed (original) (raw)
Comment
Elevated FUS levels by overriding its autoregulation produce gain-of-toxicity properties that disrupt protein and RNA homeostasis
Wan Yun Ho et al. Autophagy. 2019 Sep.
Abstract
Coding or non-coding mutations in FUS (fused in sarcoma) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition to familial ALS, abnormal aggregates of FUS are present in a portion of FTD and other neurodegenerative diseases independent of their mutations. Broad expression within the central nervous system of either wild-type or two ALS-linked human FUS mutants produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated to maintain an optimal steady-state level. Increasing FUS expression by saturating its autoregulatory mechanism results in rapidly progressive neurological phenotypes and dose-dependent lethality. Genome-wide expression analysis reveals genetic mis-regulations distinct from those via FUS reduction. Among these are increased expression of lysosomal proteins, suggestive of disruption in protein homeostasis as a potential gain-of-toxicity mechanism. Indeed, increased expression of wild-type FUS or ALS-linked mutant forms of FUS inhibit macroautophagy/autophagy. Collectively, our results demonstrate that: (1) mice expressing FUS develop progressive motor deficits, (2) increased FUS expression by overriding its autoregulatory mechanism accelerates neurodegeneration, providing a basis for FUS involvement without mutation, and (3) disruption in both protein homeostasis and RNA processing contribute to FUS-mediated toxicity.
Keywords: Amyotrophic lateral sclerosis (ALS); FUS; SQSTM1/p62; autophagy; frontotemporal dementia (FTD); lysosome; p62.
Figures
Figure 1.
Proposed model of FUS-mediated neurodegeneration. FUS homeostasis is essential for maintaining both protein and RNA homeostasis. FUS protein binds directly to FUS mRNA. The FUS level is possibly maintained through nonsense-mediated decay and/or miRNA-mediated mechanisms. An elevated FUS level produces both gain-of-toxicity properties (by either increasing proteotoxic stress through autophagy inhibition or expression of stress genes), and loss of RNA-processing function affecting genes involved with long transcripts and synaptic regulation. Together these changes cause neuronal and synaptic dysfunction and eventual neuronal death.
Comment on
- Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.
Ling SC, Dastidar SG, Tokunaga S, Ho WY, Lim K, Ilieva H, Parone PA, Tyan SH, Tse TM, Chang JC, Platoshyn O, Bui NB, Bui A, Vetto A, Sun S, McAlonis-Downes M, Han JS, Swing D, Kapeli K, Yeo GW, Tessarollo L, Marsala M, Shaw CE, Tucker-Kellogg G, La Spada AR, Lagier-Tourenne C, Da Cruz S, Cleveland DW. Ling SC, et al. Elife. 2019 Feb 12;8:e40811. doi: 10.7554/eLife.40811. Elife. 2019. PMID: 30747709 Free PMC article.
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This work was supported by the Ministry of Education, Singapore [MOE2016-T2-1-024]; National Medical Research Council, Singapore [NMRC/OFIRG/0042/2017]; National Medical Research Council, Singapore [NMRC/OFIRG/0001/2016].
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