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Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

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dc.contributor.author Crook, Zachary Ryan
dc.contributor.author Housman, David E.
dc.date.accessioned 2012-11-15T20:38:39Z
dc.date.available 2012-11-15T20:38:39Z
dc.date.issued 2012-04
dc.date.submitted 2012-01
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/1721.1/74657
dc.description.abstract The ability to quantitatively evaluate the impact of a potential therapeutic intervention for Huntington disease (HD) in animal models for the disease is a critical step in the pathway to development of an effective therapy for this devastating neurodegenerative disorder. We report here an approach that combines a cell-based assay’s quantitative accuracy and direct relationship to molecular processes with the ability to directly monitor effects in HD model mouse neurons. To accomplish this goal, we have developed an accurate quantitative reporter assay for a transcript known to be down-regulated as an early consequence of mutant huntingtin expression. This system uses mouse strains carrying a GFP reporter for the expression of the dopamine receptor D2, expressed in the medium spiny neurons of the basal ganglion. This receptor consistently demonstrates reduced expression in patients and murine models, and the FACS-based assay gives a highly accurate and quantitative readout of this pathology in mouse neurons expressing mutant huntingtin. For four genetic models and one viral model, a highly reproducible time course of loss of reporter expression is observed. This quantitative measure of HD pathology can be used to measure the effects of HD therapeutics in small cohorts with high confidence. We further demonstrate that the introduction of an shRNA against the huntingtin transgene by virus can improve this pathological status in medium spiny neurons transduced with the construct. We believe this system can be of great utility in the validation of effective therapeutic interventions for HD. en_US
dc.description.sponsorship National Institutes of Health (U.S.). Nanomedicine Development Centers (PN2) (Award NOT-RM-05-010) en_US
dc.language.iso en_US
dc.publisher National Academy of Sciences en_US
dc.relation.isversionof http://dx.doi.org/10.1073/pnas.1204542109 en_US
dc.rights Article 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.source PNAS en_US
dc.title Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice en_US
dc.type Article en_US
dc.identifier.citation Crook, Z. R., and D. E. Housman. “Dysregulation of Dopamine Receptor D2 as a Sensitive Measure for Huntington Disease Pathology in Model Mice.” Proceedings of the National Academy of Sciences 109.19 (2012): 7487–7492. ©2012 by the National Academy of Sciences en_US
dc.contributor.department Massachusetts Institute of Technology. Dept. of Biology en_US
dc.contributor.department David H. Koch Institute for Integrative Cancer Research at MIT en_US
dc.contributor.mitauthor Crook, Zachary Ryan
dc.contributor.mitauthor Housman, David E.
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Final published version en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Crook, Z. R.; Housman, D. E. en


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