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dc.contributor.authorKrench, Megan A.
dc.contributor.authorCho, Richard W.
dc.contributor.authorLittleton, J. Troy
dc.date.accessioned2017-01-18T15:34:58Z
dc.date.available2017-01-18T15:34:58Z
dc.date.issued2016-05
dc.date.submitted2016-04
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttp://hdl.handle.net/1721.1/106522
dc.description.abstractHuntington disease-like 2 (HDL2) and Huntington disease (HD) are adult-onset neurodegenerative diseases characterized by movement disorders, psychiatric disturbances and cognitive decline. Brain tissue from HD and HDL2 patients shows degeneration of the striatum and ubiquitinated inclusions immunoreactive for polyglutamine (polyQ) antibodies. Despite these similarities, the diseases result from different genetic mutations. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene, while HDL2 results from an expansion at the junctophilin 3 (JPH3) locus. Recent evidence indicates that the HDL2 expansion may give rise to a toxic polyQ protein translated from an antisense mRNA derived from the JPH3 locus. To investigate this hypothesis, we generated and characterized a Drosophila HDL2 model and compared it with a previously established HD model. We find that neuronal expression of HDL2-Q15 is not toxic, while the expression of an expanded HDL2-Q138 protein is lethal. HDL2-Q138 forms large nuclear aggregates, with only smaller puncta observed in the cytoplasm. This is in contrast to what is observed in a Drosophila model of HD, where polyQ aggregates localize exclusively to the cytoplasm. Altering localization of HLD2 with the addition of a nuclear localization or nuclear export sequence demonstrates that nuclear accumulation is required for toxicity in the Drosophila HDL2 model. Directing HDL2-Q138 to the nucleus exacerbates toxicity in multiple tissue types, while confining HDL2-Q138 to the cytoplasm restores viability to control levels. We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms are likely to drive toxicity in Drosophila models of these disorders.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grants NS40296 and MH104536)en_US
dc.description.sponsorshipJPB Foundationen_US
dc.language.isoen_US
dc.publisherOxford University Pressen_US
dc.relation.isversionofhttp://dx.doi.org/10.1093/hmg/ddw166en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourceProf. Littleton via Courtney Crummetten_US
dc.titleA Drosophila model of Huntington disease-like 2 exhibits nuclear toxicity and distinct pathogenic mechanisms from Huntington diseaseen_US
dc.typeArticleen_US
dc.identifier.citationKrench, Megan, Richard W. Cho, and J. Troy Littleton. “A Drosophila Model of Huntington Disease-like 2 Exhibits Nuclear Toxicity and Distinct Pathogenic Mechanisms from Huntington Disease.” Human Molecular Genetics 25.15 (2016): 3164–3177.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentPicower Institute for Learning and Memoryen_US
dc.contributor.approverLittleton, J Troyen_US
dc.contributor.mitauthorKrench, Megan A.
dc.contributor.mitauthorCho, Richard W.
dc.contributor.mitauthorLittleton, J. Troy
dc.relation.journalHuman Molecular Geneticsen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsKrench, Megan; Cho, Richard W.; Littleton, J. Troyen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-7762-5303
dc.identifier.orcidhttps://orcid.org/0000-0001-5576-2887
mit.licenseOPEN_ACCESS_POLICYen_US


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