dc.contributor.author | Zheng, Shuqiu | |
dc.contributor.author | Ghitani, Nima | |
dc.contributor.author | Blackburn, Jessica S | |
dc.contributor.author | Liu, Jeh-Ping | |
dc.contributor.author | Zeitlin, Scott O | |
dc.date.accessioned | 2013-04-22T15:53:52Z | |
dc.date.issued | 2012 | |
dc.identifier.citation | Zheng, 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.issn | 1756-6606 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:10579204 | |
dc.description.abstract | Background: 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.iso | en_US | en_US |
dc.publisher | BioMed Central | en_US |
dc.relation.isversionof | doi:10.1186/1756-6606-5-28 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499431/pdf/ | en_US |
dash.license | LAA | |
dc.subject | Huntingtin | en_US |
dc.subject | Epitope tag | en_US |
dc.subject | Knock-in | en_US |
dc.subject | Polyglutamine | en_US |
dc.subject | Proline-rich region | en_US |
dc.subject | Sequestration | en_US |
dc.subject | Huntington’s disease | en_US |
dc.title | 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 | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | Molecular Brain | en_US |
dash.depositing.author | Blackburn, Jessica S | |
dc.date.available | 2013-04-22T15:53:52Z | |
dc.identifier.doi | 10.1186/1756-6606-5-28 | * |
dash.contributor.affiliated | Blackburn, Jessica S. | |