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dc.contributor.authorWu, Chaohong
dc.contributor.authorHong, Pengyu
dc.contributor.authorSchulte, Joost
dc.contributor.authorSepp, Katharine J.
dc.contributor.authorLittleton, J. Troy
dc.date.accessioned2012-02-15T17:28:31Z
dc.date.available2012-02-15T17:28:31Z
dc.date.issued2011-08
dc.date.submitted2011-02
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/1721.1/69109
dc.description.abstractTo identify Huntington's Disease therapeutics, we conducted high-content small molecule and RNAi suppressor screens using a Drosophila primary neural culture Huntingtin model. Drosophila primary neurons offer a sensitive readout for neurotoxicty, as their neurites develop dysmorphic features in the presence of mutant polyglutamine-expanded Huntingtin compared to nonpathogenic Huntingtin. By tracking the subcellular distribution of mRFP-tagged pathogenic Huntingtin and assaying neurite branch morphology via live-imaging, we identified suppressors that could reduce Huntingtin aggregation and/or prevent the formation of dystrophic neurites. The custom algorithms we used to quantify neurite morphologies in complex cultures provide a useful tool for future high-content screening approaches focused on neurodegenerative disease models. Compounds previously found to be effective aggregation inhibitors in mammalian systems were also effective in Drosophila primary cultures, suggesting translational capacity between these models. However, we did not observe a direct correlation between the ability of a compound or gene knockdown to suppress aggregate formation and its ability to rescue dysmorphic neurites. Only a subset of aggregation inhibitors could revert dysmorphic cellular profiles. We identified lkb1, an upstream kinase in the mTOR/Insulin pathway, and four novel drugs, Camptothecin, OH-Camptothecin, 18β-Glycyrrhetinic acid, and Carbenoxolone, that were strong suppressors of mutant Huntingtin-induced neurotoxicity. Huntingtin neurotoxicity suppressors identified through our screen also restored viability in an in vivo Drosophila Huntington's Disease model, making them attractive candidates for further therapeutic evaluation.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant R01 EB007042)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pone.0023841en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleHigh-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington's Disease Modelen_US
dc.typeArticleen_US
dc.identifier.citationSchulte, Joost et al. “High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington’s Disease Model.” Ed. Mark R. Cookson. PLoS ONE 6.8 (2011): e23841. Web. 15 Feb. 2012.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. Troy
dc.contributor.mitauthorSchulte, Joost
dc.contributor.mitauthorSepp, Katharine J.
dc.contributor.mitauthorLittleton, J. Troy
dc.relation.journalPLoS ONEen_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.orderedauthorsSchulte, Joost; Sepp, Katharine J.; Wu, Chaohong; Hong, Pengyu; Littleton, J. Troyen
dc.identifier.orcidhttps://orcid.org/0000-0001-5576-2887
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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