ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.
Bottom Line: One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation.Nuclear FUS granules may be similarly affected.Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
Affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.Show MeSH
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Mentions: To rigorously test the idea that mutations in FUS alter its assembly into RNP granules, we first explored the biology of FUS in a C. elegans model of FUS proteinopathy (Murakami et al., 2012). In this model, equivalent levels of wild-type or mutant human FUS protein are expressed under the neuron-specific Prgef-1 promoter with a GFP tag, which does not alter the activity or location of FUS (Murakami et al., 2012). We focused on animals (n ≥ 3 lines per mutant) expressing wild-type FUS (FUS(WT)) or one of five ALS/FTD mutants: FUS (R495X), FUS(R522G), FUS(R524S), FUS(P525L), and FUS501(which models several ALS/FTD-associated C-terminal truncating mutations) (Figure 1A). These mutations span a wide range of predicted aggregation propensities as calculated using the Zyggregator method (Tartaglia and Vendruscolo, 2008): FUS(R495X): Zagg = 0.44; FUS(R522G): Zagg = 0.09; FUS(R524S): Zagg = 0.05; FUS(P525L): Zagg = 0.12; FUS501: Zagg = 0.52 (Figure S4). The aggregation propensities of these mutants correlate with their phenotypic severities in C. elegans and in humans, ranging from mild (R522G) to severe (FUS (P525L), FUS (R495X), and FUS501) (Murakami et al., 2012) (Figure S5).
Affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.