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dc.contributor.authorSathasivam, Kirupa
dc.contributor.authorNeueder, Andreas
dc.contributor.authorGipson, Theresa Anne
dc.contributor.authorLandles, Christian
dc.contributor.authorBenjamin, Agnesska C.
dc.contributor.authorBondulich, Marie K.
dc.contributor.authorAmith, Donna L.
dc.contributor.authorFaull, Richard L. M.
dc.contributor.authorRoos, Raymund A. C.
dc.contributor.authorHowland, David
dc.contributor.authorDetloff, Peter J.
dc.contributor.authorHousman, David E.
dc.contributor.authorBates, Gillian P.
dc.date.accessioned2013-08-08T18:48:24Z
dc.date.available2013-08-08T18:48:24Z
dc.date.issued2013-01
dc.date.submitted2012-12
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/79814
dc.description.abstractHuntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length–dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings.en_US
dc.description.sponsorshipCure Huntington’s Disease Initiative, Inc.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1221891110en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleAberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington diseaseen_US
dc.typeArticleen_US
dc.identifier.citationSathasivam, K., A. Neueder, T. A. Gipson, C. Landles, A. C. Benjamin, M. K. Bondulich, D. L. Smith, et al. “Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease.” Proceedings of the National Academy of Sciences 110, no. 6 (February 5, 2013): 2366-2370.en_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorGipson, Theresa Anneen_US
dc.contributor.mitauthorHousman, David E.en_US
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsSathasivam, K.; Neueder, A.; Gipson, T. A.; Landles, C.; Benjamin, A. C.; Bondulich, M. K.; Smith, D. L.; Faull, R. L. M.; Roos, R. A. C.; Howland, D.; Detloff, P. J.; Housman, D. E.; Bates, G. P.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-0524-5301
dc.identifier.orcidhttps://orcid.org/0000-0001-5016-0756
mit.licensePUBLISHER_POLICYen_US


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