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Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

31 Pages Posted: 14 Mar 2019 Sneak Peek Status: Published

See all articles by Haiyan An

Haiyan An

Cardiff University - Biomedicine division

Lucy Skelt

Cardiff University - Biomedicine division

Vladimir L. Buchman

Cardiff University - Biomedicine division

Tatyana Shelkovnikova

Cardiff University - Biomedicine division; Cardiff University - Medicines Discovery Institute

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Abstract

Mutations in the fused in sarcoma (FUS) gene cause a subset of familial amyotrophic lateral sclerosis cases (ALS-FUS). Mutant FUS mislocalises to the cytoplasm of neurons and glia, where it eventually becomes deposited in a form of insoluble inclusions, thus marking the onset of FUS proteinopathy. Mutant FUS has high affinity to cytoplasmic RNA granules stress granules (SGs), and can also spontaneously form small RNA granules, which grow under conditions of stress. It is believed that stress-induced mutant FUS assemblies may become precursors of pathological inclusions, however the nature of stress which acts as a trigger for FUS proteinopathy is still elusive. To address this, we characterised the ability of known SG-inducing stresses to cause sustained presence of mutant FUS-enriched cytoplasmic assemblies. Using CRISPR/Cas9 cell lines expressing endogenous mutant FUS, we found that single application of a viral infection mimetic compound, synthetic double-stranded (ds) RNA poly(I:C), is sufficient to cause formation of cytoplasmic FUS-containing assemblies which persist in cells for up to 48 hours. These FUS assemblies sequester the autophagy receptor optineurin and nucleocytoplasmic transport factors including FUS import receptor, Transportin 1. Moreover, mutant FUS expressing cells, including patient fibroblasts, are hypersensitive to dsRNA toxicity. Finally, we found that an integral component of the antiviral immune response, type I interferon, promotes FUS protein accumulation by increasing its mRNA stability. Our data suggest that antiviral immune response can expedite the onset and progression of FUS proteinopathy by promoting FUS protein accumulation and its coalescence into persistent cytoplasmic aggregates.

Keywords: fused in sarcoma (FUS), amyotrophic lateral sclerosis (ALS), stress granule, RNA granule, FUS proteinopathy, antiviral response, dsRNA, optineurin, nucleoplasmic transport

Suggested Citation

An, Haiyan and Skelt, Lucy and Buchman, Vladimir L. and Shelkovnikova, Tatyana, Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis (March 14, 2019). Available at SSRN: https://ssrn.com/abstract=3351828 or http://dx.doi.org/10.2139/ssrn.3351828
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Haiyan An

Cardiff University - Biomedicine division

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Lucy Skelt

Cardiff University - Biomedicine division

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Vladimir L. Buchman

Cardiff University - Biomedicine division ( email )

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Tatyana Shelkovnikova (Contact Author)

Cardiff University - Biomedicine division ( email )

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Cardiff University - Medicines Discovery Institute ( email )

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

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