Molecular Mechanisms Underlying Neuropathology in Mouse Models of Huntington’s Disease

Huntington’s disease (HD) is the most common dominantly-inherited neurodegenerative disease and affects roughly 30,000 patients in the United States, with another 150,000 at risk for developing the disease. HD is caused by an expanded polyglutamine repeat in the Huntingtin protein, which is encoded by an expanded CAG repeat in the Huntingtin gene. HD causes severe and relatively selective death of striatal medium-sized spiny neurons and cortical pyramidal neurons, leading to the typically mid-age onset of a clinical triad of symptoms: motor dysfunction, cognitive decline, and psychiatric disturbances, although the age of onset is variable and inversely correlated with the length of CAG repeat. Much work characterizing mechanisms underlying HD pathogenesis has come from the development of genetic mouse models of the disease. This dissertation will detail work performed in characterizing the cellular and molecular determinants of HD pathogenesis in novel mouse models developed in the Yang lab. We have used conditional genetics to define cells in the cortex and striatum as essential to developing HD phenotypes, then assessed molecular signatures in these cells that are dependent on the mutant huntingtin protein. Further, we have used mice in which the N17 domain, which is critical for exclusion of small, toxic huntingtin fragments from the nucleus, to assess the effects of nuclear mutant huntingtin on the development of disease-related phenotypes including behavior, neuropathology, and transcriptionopathy. Work in this thesis helps lead to the bases underlying the pathology of HD, as well as informing future studies aimed at developing therapeutic interventions