Thesis (Ph. D.)--University of California, San Diego, 2000. / Vita. Includes bibliographical references (leaves 165-180).

Thesis (Ph. D.)--University of Virginia, 2006. / Includes bibliographical references. Also available online through Digital Dissertations.

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder of typically mid-life onset, for which there is currently no cure. HD is one of nine neurological disorders caused by the expansion of a CAG trinucleotide repeat that encodes an extended polyglutamine tract within the respective disease proteins (which, in the case of HD, is Huntingtin). Curiously, despite these proteins having mostly widespread patterns of expression in the brain, a specific subset of neurons is preferentially affected in each disease, whilst other neurons also expressing the mutant protein are relatively unaffected. Furthermore, although the expression patterns of these disease proteins often overlap in distribution within the brain, the population of neurons that is most vulnerable differs from one disease to the next. Knowledge of what determines the specificity of neuronal vulnerability is likely to provide insight into the molecular mechanism(s) underlying the pathology in these diseases. The aim of this work was to use the zebrafish model organism to investigate two factors hypothesised to contribute to the specificity of neuronal vulnerability in HD: 1) region-specific somatic expansion of the disease allele, and 2) disruption of normal Huntingtin (Htt) protein function. The most significant findings of this study resulted from the investigation into the normal function of Htt. Antisense morpholino oligonucleotides were used to specifically knock down Htt expression in early zebrafish development, resulting in a wide variety of developmental defects. Most notably, Htt-deficient zebrafish had pale blood due to a decrease in haemoglobin production, despite the presence of (apparently unavailable) iron within these cells. Provision of additional iron in a bio-available form to the cytoplasm restored haemoglobin production in Htt-deficient embryos. Since blood cells acquire iron via receptor-mediated endocytosis of transferrin, these results suggest a role for Htt in the release of iron from endocytic compartments into the cytosol. Iron is required for the function of many cellular proteins and enzymes that play key roles in oxidative energy production. Disrupted iron homeostasis and decreased energy metabolism are features of HD pathogenesis that correlate to the major sites of degeneration in the HD brain. The findings of this study raise the possibility that perturbation of normal Htt function (by polyglutamine expansion) may contribute to these defects, thereby providing a novel link between Htt function and specificity of neuronal vulnerability in HD. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1274748 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

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Several new techniques were developed to assess quantitatively the degree to which patients with Huntington's disease (HD) are aware of their deficits, to evaluate the relation between cognitive impairment and unawareness of deficits, and to determine whether patients exhibit differential awareness of their motor disturbance and cognitive deficits. Results of a questionnaire measure indicated that HD patients rated their own difficulties with motor and cognitive activities of daily life significantly lower than relatives rated patients' problems, and this discrepancy was related to patients' level of cognitive impairment. In contrast, patients were reasonably accurate when predicting their performance on specific motor and cognitive tasks when compared to both their actual performance and relatives' predictions. Several interpretations of these findings are discussed, and the role of frontal lobe dysfunction in the awareness problems characterizing dementia is considered.

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The debate on genetic testing for Huntington???s disease has been dominated heavily by the bioethical and biomedical discourses. Yet upon analysis, both discourses are highly inadequate for understanding the complexity of the difficult choices people are faced with, and the inter-personal relations that are central to decisions regarding the uptake of genetic tests. The purpose of this thesis is two-fold. Firstly, to conduct a theoretically-informed critical analysis of the existing bioethical discourse on genetic testing for Huntington???s disease, that draws primarily on the work of contemporary feminist thinkers. Secondly, to explore how people with a genetic risk for Huntington???s disease negotiate the available choices between certainty and uncertainty; how they experience the liminality of ???being at risk??? in everyday life; how they manage their social environments; and how they interpret their own situation. The matter of ???choice??? is heightened because of the ready availability of genetic testing for Huntington???s disease, and the moral rhetoric that accompanies the provision of genetic services. Empirically, the research draws on the narratives by eleven people with a family history of Huntington???s disease, through which they discuss their fears of living in the shadow of the fatal disease, and consider their choices on reproduction and genetic testing. Their narratives will be analysed through the work of Foucault and Goffman, as well as a wide range of contemporary sociologists.The thesis being proposed is that decisions on genetic testing cannot be said to be ???individual???, but are instead dispersed among the social relations between the self and others, reflecting and transforming the values, competing desires, and the discourses that are prevalent in their social worlds. This is achieved through the discursive production of a web of narratives through which both individuals and institutions attempt to govern, with varying degrees of success, the implications of this relatively new field of knowledge.

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Alterations in both structural and synaptic plasticity in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated if hippocampal plasticity is affected in the transgenic YAC128 mouse model of Huntington disease (HD). Reductions in adult hippocampal neurogenesis were observed in the dentate gyrus (DG) of early symptomatic to end-stage mice compared with wild-type (WT) controls, however there were no changes in cell proliferation and differentiation in the subventricular zone. Early symptomatic mice also displayed attenuated paired-pulse plasticity and long-term depression in the DG, while long-term potentiation was found to be normal in YAC128 mice. The changes in hippocampal plasticity may contribute to the cognitive abnormalities observed in these animals. / Graduate / 0306