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UBC Theses and Dissertations

Characterization and treatment of mouse models of Huntington disease Van Raamsdonk, Jeremy Michael


Huntington disease (HD) is an adult onset neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment and neuropsychiatric disturbances. HD patients exhibit progressive and selective neurodegeneration primarily in the striatum and cortex. There is currently no treatment that can prevent the development of HD or alter its progression. The major objectives of this thesis were to determine which symptoms of HD are recapitulated in Y A C transgenic mouse models of the disease, to develop a standardized protocol for therapeutic trials in these mice and to investigate potential treatments for HD. Two transgenic mouse models of HD were examined that express huntingtin (htt) with either 72 (YAC72 mice) or 128 (YAC128 mice) glutamines from a yeast artificial chromosome transgene. While YAC72 mice exhibit a mild phenotype, YAC128 mice show quantifiable abnormalities that recapitulate the motor and cognitive deficits in HD. Importantly, YAC128 mice also exhibit selective and progressive degeneration in the brain, including neuronal loss. To determine the feasibility of genetic modulation of the disease phenotype, we investigated the ability of over-expression of wild type htt to prevent striatal neuropathology in YAC128 mice based on a putative pro-survival function of wild type htt. We demonstrate for the first time that wild type htt is neuroprotective in the brain. In YAC128 mice, over-expression of wild type htt prevented atrophy of striatal neurons(but did not significantly improve striatal volume or striatal neuronal numbers. To determine the feasibility of pharmacologic therapeutic trials in YAC128 mice we treated mice with cystamine, a transglutaminase inhibitor with other beneficial characteristics. While cystamine treatment did not improve motor symptoms, this treatment ameliorated striatal volume loss, striatal neuronal loss and striatal neuronal atrophy. This trial validates the use of YAC128 mice in therapeutic trials for HD as we reproduced all of the differences between YAC128 and WT mice in this therapeutic trial. Overall, this thesis demonstrates that the YAC128 mouse model of HD recapitulates the progressive motor dysfunction, cognitive deficits and selective neurodegeneration of HD. As such, these mice can be used for studies of HD pathogenesis and in preclinical therapeutic trials for HD.

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