Elevated FUS levels by overriding its autoregulation produce gain-of-toxicity properties that disrupt protein and RNA homeostasis - PubMed (original) (raw)

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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.

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Figure 1.

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.

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References

    1. Ling S-C, Dastidar SG, Tokunaga S, et al. Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis. Elife. 2019;8:602. - PMC - PubMed

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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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