Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease

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dc.contributor.authorGomez Pastor, Rocio
dc.contributor.authorBurchfiel, Eileen T.
dc.contributor.authorNeef, Daniel W.
dc.contributor.authorJaeger, Alex M.
dc.contributor.authorCabiscol Català, Elisa
dc.contributor.authorMcKinstry, Spencer U.
dc.contributor.authorDoss, Argenia
dc.contributor.authorAballay, Alejandro
dc.contributor.authorLo, Donald C.
dc.contributor.authorAkimov, Sergey S.
dc.contributor.authorRoss, Christopher A.
dc.contributor.authorEroglu, Cagla
dc.contributor.authorThiele, Dennis J.
dc.date.accessioned2017-02-27T11:33:27Z
dc.date.available2017-02-27T11:33:27Z
dc.date.issued2017
dc.description.abstractHuntington’s Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD.ca_ES
dc.description.sponsorshipThis work was supported by National Institutes of Health grant R01 NS065890 to D.J.T., R01 DA031833 and R01 NS096352 to C.E., R01GM070977 to A.A., U24NS069422/U24NS078378 and R21NS083365 to C.A.R., a Holland Trice Scholar Award to C.E. and D.J.T., NIH Predoctoral Fellowship F31GM119375 to E.T.B. and a Postdoctoral Fellowship from the Huntington’s Disease Society of America to R.G.P.ca_ES
dc.identifier.doihttps://doi.org/10.1038/ncomms14405
dc.identifier.idgrec025551
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10459.1/59330
dc.language.isoengca_ES
dc.publisherNatureca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1038/ncomms14405ca_ES
dc.relation.ispartofNature Communications, 2017, vol. 8, núm. 14405, p. 1-17ca_ES
dc.rightscc-by (c) Gomez, et al., 2017ca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.titleAbnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s diseaseca_ES
dc.typearticleca_ES
dc.type.versionpublishedVersionca_ES
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