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: We have previously noted that C. elegans expressing either full-length wild-type FUS or full-length mutant FUS had very few intra-cytoplasmic stress granules (zero to two per neuron; p = N.S.) (Murakami et al., 2012). However, animals expressing FUS (WT) and animals expressing mutant FUS are all clearly capable of mounting a vigorous stress response after heat shock, displaying abundant stress granules (five to six granules/cell) (Figure 8, left panel; p = N.S.). These in vivo observations suggest that (1) animals expressing mutant or wild-type FUS are capable of mounting a stress response and (2) mutant-expressing animals are not more stressed by accumulation of misfolded mutant FUS than are animals expressing wild-type FUS.
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.