ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Murakami, Tetsuro
• dc.contributor.author Gaetano Tartaglia, Gian
• dc.contributor.author George-Hyslop, Peter St
• dc.date.accessioned 2024-03-26T07:13:52Z
• dc.date.available 2024-03-26T07:13:52Z
• dc.date.issued 2015
• dc.description.abstract 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.
• dc.description.sponsorship Supported by Canadian Institutes of Health Research (P.E.F. and P.S.G.-H.), Alzheimer Society of Ontario (P.E.F., P.St.G.H.), Wellcome Trust (P.S.G.-H., M.V., C.F.K., G.S.K.S., D.R., and C.H.), Medical Research Council (P.S.G.-H., M.V., C.F.K., and G.S.K.S.), NIH Research, Alzheimer Research UK (C.F.K. and G.S.K.S.), Gates Cambridge Scholarship (J.Q.L.), Engineering and Physical Sciences Research Council (C.F.K. and G.S.K.S.), European Research Council Starting Grant RIBOMYLOME_309545 (G.G.T.), European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 322817 (C.H.), and National Institute of Neurological Disorders and Stroke R01 NS07377 (N.A.S.). The authors thank Tom Cech and Roy Parker for helpful discussions.
• dc.format.mimetype application/pdf
• dc.identifier.citation Murakami T, Qamar S, Lin JQ, Schierle GSK, Rees E, Miyashita A, et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron. 2015 Nov 18;88(4):678-90. DOI: 10.1016/j.neuron.2015.10.030
• dc.identifier.doi http://dx.doi.org/10.1016/j.neuron.2015.10.030
• dc.identifier.issn 0896-6273
• dc.identifier.uri http://hdl.handle.net/10230/59565
• dc.language.iso eng
• dc.publisher Cell Press
• dc.relation.ispartof Neuron. 2015 Nov 18;88(4):678-90
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/322817
• dc.rights This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Neurotoxicologia
• dc.subject.other Demència
• dc.subject.other Mutació (Biologia)
• dc.title ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion