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ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.



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Murakami, Tetsuro 
Qamar, Seema 
Lin, Julie Qiaojin 
Schierle, Gabriele S Kaminski 


The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. 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.



Amyotrophic Lateral Sclerosis, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cytoplasmic Granules, Disease Models, Animal, Frontotemporal Lobar Degeneration, Hydrogels, Longevity, Motor Activity, Mutation, Phase Transition, RNA, Messenger, RNA-Binding Protein FUS, Ribonucleoproteins

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Elsevier BV
European Research Council (322817)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Medical Research Council (G0902243)
Medical Research Council (MR/K02292X/1)
Medical Research Council (MC_G1000734)
Wellcome Trust (084812/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (089703/Z/09/Z)
Wellcome Trust (081864/Z/06/Z)
Supported by Canadian Institutes of Health Research (PEF, PStGH), Alzheimer Society of Ontario (PEF, PStGH), Wellcome Trust (PStGH, MEV, CFK, GSK, DR, CEH), Medical Research Council (PStGH, MEV, CFK, GSK), National Institutes of Health Research, Alzheimer Research UK (CFK, GSK), Gates Cambridge Scholarship (JQL), Engineering and Physical Sciences Research Council (CFK, GSK), European Research Council Starting Grant RIBOMYLOME_309545 (GGT), European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement no. 322817 (CEH), and National Institute of Neurological Disorders and Stroke R01 NS07377 (NAS). The authors thank Tom Cech and Roy Parker for helpful discussions.