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dc.contributor.authorZheng, Shuqiu
dc.contributor.authorGhitani, Nima
dc.contributor.authorBlackburn, Jessica S
dc.contributor.authorLiu, Jeh-Ping
dc.contributor.authorZeitlin, Scott O
dc.date.accessioned2013-04-22T15:53:52Z
dc.date.issued2012
dc.identifier.citationZheng, Shuqiu, Nima Ghitani, Jessica S. Blackburn, Jeh-Ping Liu, and Scott O. Zeitlin. 2012. A series of N-terminal epitope tagged Hdh knock-in alleles expressing normal and mutant huntingtin: Their application to understanding the effect of increasing the length of normal huntingtin’s polyglutamine stretch on CAG140 mouse model pathogenesis. Molecular Brain 5(1): 28.en_US
dc.identifier.issn1756-6606en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10579204
dc.description.abstractBackground: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ) stretch within Huntingtin (htt), the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR) in modulating HD mouse model pathogenesis is currently unknown. Results: We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh) encoding N-terminal hemaglutinin (HA) or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt) and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt). Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q- htt and mutant (140Q) htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt’s polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. Conclusion: In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi:10.1186/1756-6606-5-28en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499431/pdf/en_US
dash.licenseLAA
dc.subjectHuntingtinen_US
dc.subjectEpitope tagen_US
dc.subjectKnock-inen_US
dc.subjectPolyglutamineen_US
dc.subjectProline-rich regionen_US
dc.subjectSequestrationen_US
dc.subjectHuntington’s diseaseen_US
dc.titleA Series of N-terminal Epitope Tagged Hdh Knock-In Alleles Expressing Normal and Mutant Huntingtin: Their Application to Understanding the Effect of Increasing the Length of Normal Huntingtin’s Polyglutamine Stretch on CAG140 Mouse Model Pathogenesisen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalMolecular Brainen_US
dash.depositing.authorBlackburn, Jessica S
dc.date.available2013-04-22T15:53:52Z
dc.identifier.doi10.1186/1756-6606-5-28*
dash.contributor.affiliatedBlackburn, Jessica S.


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