Show simple item record

dc.contributor.authorHogel, Matthew
dc.date.accessioned2012-11-20T15:52:39Z
dc.date.available2012-11-20T15:52:39Z
dc.date.issued2012-11-20
dc.identifier.urihttp://hdl.handle.net/10222/15723
dc.description.abstractHuntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which translocates, and accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients and is consistently observed in all animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression and an understanding of the effects of mHtt may lead to strategies to slow the progression of the disease. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of these models using two N-mHtt-affected promoters in in vitro transcription assays and in two cell models of HD using techniques including overexpression of known N-mHtt-interacting transcription factors, chromatin immunoprecipitation, promoter deletion and mutation analyses and in vitro promoter binding assays. Based on our results and those in the literature, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at affected promoters. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as the observation that some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N-mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt.en_US
dc.language.isoen_USen_US
dc.subjectHuntington'sen_US
dc.subjectTranscriptionen_US
dc.subjectRepressionen_US
dc.subjectHuntingtinen_US
dc.subjectPolyglutamineen_US
dc.subjectTranscriptional Dysregulationen_US
dc.subjectin vitro transcriptionen_US
dc.subjectN548en_US
dc.subjectST14Aen_US
dc.subjectDual-luciferase assayen_US
dc.subjectChromatin Immunoprecipitationen_US
dc.subjectPromoter Deletionen_US
dc.subjectLinker Scanning Mutagenesisen_US
dc.subjectQuantitative PCRen_US
dc.subjectPromoter binding assayen_US
dc.subjectTBPen_US
dc.subjectRAP30en_US
dc.titleINVESTIGATING THE MECHANISM OF PROMOTER-SPECIFIC N-TERMINAL MUTANT HUNTINGTIN-MEDIATED TRANSCRIPTIONAL DYSREGULATIONen_US
dc.date.defence2011-08-30
dc.contributor.departmentDepartment of Pharmacology with Neuroscienceen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerDr. Simonetta Sipioneen_US
dc.contributor.graduate-coordinatorDr. Jana Sawynoken_US
dc.contributor.thesis-readerDr. Elizabeth Cowleyen_US
dc.contributor.thesis-readerDr. George Robertsonen_US
dc.contributor.thesis-supervisorDr. Eileen Denovan-Wrighten_US
dc.contributor.ethics-approvalNot Applicableen_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.copyright-releaseNot Applicableen_US
 Find Full text

Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record