| dc.contributor.author | Hu, Haibei. | en_US |
| dc.date.accessioned | 2014-10-21T12:33:48Z | |
| dc.date.available | 2007 | |
| dc.date.issued | 2007 | en_US |
| dc.identifier.other | AAINR31498 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54961 | |
| dc.description | Inheritance of one copy of the huntingtin gene with an extended CAG repeat causes Huntington's Disease (HD). People with HD gradually develop a triad of clinical symptoms that involve motor dysfunction, cognition deficits and psychiatric disturbances. Currently, there is no effective treatment for HD. The most distinct neuropathology in HD is a gradual loss of GABAergic medium spiny projection neurons in the caudate and putamen. Studies from animal models of HD have demonstrated that the amino terminus of mutant huntingtin (N-mHtt) accumulates in the nucleus and that levels of a specific subset of mRNAs decrease in some neurons. How N-mHtt reduces synthesis of mRNA in a cell- and gene-specific manner is currently unknown. In this study, we employed a systematic approach to explore the mechanism whereby N-mHtt exerts transcriptional repression in transgenic HD mice, and in cell culture and in vitro models of HD. We chose to study phosphodiesterase 10A (PDE10A) as a model of mutant huntingtin-affected genes. We performed detailed analyses of gene structure and tissue-specific expression of PDE10A and studied the affects of N-mHtt on the expression of this gene. N-mHtt decreased transcription from the striatal-specific PDE10A2 promoter but not from a testis-specific PDE10A1 promoter. Reduced transcription was caused by decreased transcription initiation specifically from two of three transcription start sites in young R6/1 transgenic HD mice. N-mHtt present in the brains of R6/1 mice did not alter the DNA binding activities of 125 of 345 transcription factors prior to the time that transcription of PDE10A2 began to decrease. Using a cellfree system, we determined that soluble monomer form of wild-type and mutant huntingtin were associated with the transcription preinitiation complexes. Together, the data do not support the current hypotheses that N-mHtt sequesters transcription factors from promoters. Rather, it appears that N-mHtt directly associates with and may change the composition of the complexes of proteins that make up the basal transcription machinery. This direct association with the transcription machinery may block communication between the transactivation domains of promoter-specific factors and the cell-specific components in the core transcription machinery. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2007. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.title | Investigating the role of mutanthuntingtin in altered transcription in Huntington's disease. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
