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dc.contributor.authorLindquist, Susan
dc.contributor.authorSteele, Andrew D.
dc.contributor.authorWacker, Jennifer L.
dc.contributor.authorHuang, Shao-Yi
dc.contributor.authorAron, Rebecca
dc.contributor.authorLotz, Gregor P.
dc.contributor.authorNguyen, QuangVu
dc.contributor.authorGiorgini, Flaviano
dc.contributor.authorRoberson, Erik D.
dc.contributor.authorMasliah, Eliezer
dc.contributor.authorMuchowski, Paul J.
dc.date.accessioned2010-07-15T14:07:25Z
dc.date.available2010-07-15T14:07:25Z
dc.date.issued2009-07
dc.date.submitted2009-05
dc.identifier.issn0270-6474
dc.identifier.urihttp://hdl.handle.net/1721.1/56557
dc.description.abstractEndogenous protein quality control machinery has long been suspected of influencing the onset and progression of neurodegenerative diseases characterized by accumulation of misfolded proteins. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) tract in the protein huntingtin (htt), which leads to its aggregation and accumulation in inclusion bodies. Here, we demonstrate in a mouse model of HD that deletion of the molecular chaperones Hsp70.1 and Hsp70.3 significantly exacerbated numerous physical, behavioral and neuropathological outcome measures, including survival, body weight, tremor, limb clasping and open field activities. Deletion of Hsp70.1 and Hsp70.3 significantly increased the size of inclusion bodies formed by mutant htt exon 1, but surprisingly did not affect the levels of fibrillar aggregates. Moreover, the lack of Hsp70s significantly decreased levels of the calcium regulated protein c-Fos, a marker for neuronal activity. In contrast, deletion of Hsp70s did not accelerate disease in a mouse model of infectious prion-mediated neurodegeneration, ruling out the possibility that the Hsp70.1/70.3 mice are nonspecifically sensitized to all protein misfolding disorders. Thus, endogenous Hsp70s are a critical component of the cellular defense against the toxic effects of misfolded htt protein in neurons, but buffer toxicity by mechanisms independent of the deposition of fibrillar aggregates.en_US
dc.language.isoen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1523/jneurosci.2250-09.2009en_US
dc.rightsAttribution-Noncommercial-Share Alike 3.0 Unporteden_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.sourcePaul Muchowskien_US
dc.titleLoss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Diseaseen_US
dc.typeArticleen_US
dc.identifier.citationWacker, Jennifer L. et al. “Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease.” J. Neurosci. 29.28 (2009): 9104-9114.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentWhitehead Institute for Biomedical Researchen_US
dc.contributor.approverLindquist, Susan
dc.contributor.mitauthorLindquist, Susan
dc.contributor.mitauthorSteele, Andrew D.
dc.relation.journalJournal of Neuroscienceen_US
dc.eprint.versionAuthor's final manuscript
dc.type.urihttp://purl.org/eprint/type/SubmittedJournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsWacker, J. L.; Huang, S.-Y.; Steele, A. D.; Aron, R.; Lotz, G. P.; Nguyen, Q.; Giorgini, F.; Roberson, E. D.; Lindquist, S.; Masliah, E.; Muchowski, P. J.en
dc.identifier.orcidhttps://orcid.org/0000-0003-1307-882X
mit.licenseOPEN_ACCESS_POLICYen_US
mit.metadata.statusComplete


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