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

Compared with saline injected controls, rats with bilateral injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor activity, increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of local neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extrinisic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed similarity of KA-induced striatal lesions with those found in the caudate-putamen of patients with Huntington's disease (HD). The present results demonstrate that KA striatal lesioned rats also show behavioral and pharmacological similarities with HD patients. In addition, they support the view that HD is characterized by a "subcortical dementia syndrome". A review of HD is also presented. / Medicine, Faculty of / Graduate

Amino acids and other ninhydrin-positive compounds were measured in post-mortem thalamus from 25 Huntington's choreics, 10 schizophrenics, 5 schizophrenic-like psychotics, and 23 controls dying without neurological disease. Gamma-aminobutyric acid (GABA) was significantly reduced in choreic thalami, in accord with deficiencies found in other brain regions choreics (Perry et al., 1973a,b). GABA was also significantly reduced in schizophrenic thalami, suggesting a biochemical link between these two diseases, and supporting the hypothesis of a defect in the GABA system in schizophrenia (Roberts, 1972). Homocarnosine, a GABA-containing dipeptide, was also low in choreic and 9 out of 10 schizophrenic thalami. One schizophrenic had extremely high homocarnosine. Glycerophosphoethanolamine was significantly elevated in Huntington's choreics, but not in schizophrenics. A number of other variables were considered for their potential influence on amino acid concentrations in thalamus. The majority of amino acids were found to rise in a significantly linear fashion in the interval 3 to 49 hours post-mortem, although other models might have described the change better. GABA, ornithine, histidine and tyrosine were found to decrease significantly with increasing age between 21 and 80 years, in controls. The effects of pre-mortem hypoxia, regional variation within the thalamus, and neuroleptic drug treatment could not be rigorously tested with these data. Neuroleptics were unlikely to have been the cause of group differences in GABA concentration, since they failed to deplete GABA in brain of chronically treated rats. On the other hand, bronchopneumonia and other causes of pre-mortem hypoxia could not be ruled out as potential contributers to reduced GABA in thalamus. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

Adolescence is a time when individuals begin to explore and examine psychological characteristics of the self in order to discover who they really are and how they fit in the social world in which they live. It is during this time of self-exploration that adolescents at risk for Huntington's Disease often learn of their risk status and witness the debilitating symptoms of the disease in their parents. Huntington Disease (HD) is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. This dissertation investigated how adolescents experience living in a family with Huntington's Disease and therefore at risk for Huntington's Disease, and how this impacts their self-understanding and self-identity. The method of inquiry was based on a phenomenological approach. In-depth interviews were conducted with each of the adolescents. The data were analyzed using Van Manen's (1980) and Cochran and Claspell's (1987) format, resulting in an extraction of three themes. These themes are: (1) Naming the Legacy: Understanding and Misunderstanding; (2) Experiencing the Legacy: Huntington's Disease in Relation to Relationships; and (3) Integrating the Legacy: At the Crossroads of Self and Future Self. The analysis emphasizes that the at-risk adolescents' exploration of self-identity and future self was an individual process influenced by the cognitive, developmental, and socio-cultural contexts of the adolescents' lives. The process of learning about Huntington's Disease occurred through intuition and practical and experiential learning. The adolescents found support outside their family through friends and adult mentors. They engaged in complicated coping strategies and demonstrated a capacity for decision-making that displayed maturity beyond what would be expected for their age group. These findings led to specific recommendations for theory, research, and clinical practice in the area of the adolescent experience of HD. The research underscores the need for healthcare professionals to re-evaluate their view of adolescent autonomy and capacity for decision-making.

Adolescence is a time when individuals begin to explore and examine psychological characteristics of the self in order to discover who they really are and how they fit in the social world in which they live. It is during this time of self-exploration that adolescents at risk for Huntington's Disease often learn of their risk status and witness the debilitating symptoms of the disease in their parents. Huntington Disease (HD) is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. This dissertation investigated how adolescents experience living in a family with Huntington's Disease and therefore at risk for Huntington's Disease, and how this impacts their self-understanding and self-identity. The method of inquiry was based on a phenomenological approach. In-depth interviews were conducted with each of the adolescents. The data were analyzed using Van Manen's (1980) and Cochran and Claspell's (1987) format, resulting in an extraction of three themes. These themes are: (1) Naming the Legacy: Understanding and Misunderstanding; (2) Experiencing the Legacy: Huntington's Disease in Relation to Relationships; and (3) Integrating the Legacy: At the Crossroads of Self and Future Self. The analysis emphasizes that the at-risk adolescents' exploration of self-identity and future self was an individual process influenced by the cognitive, developmental, and socio-cultural contexts of the adolescents' lives. The process of learning about Huntington's Disease occurred through intuition and practical and experiential learning. The adolescents found support outside their family through friends and adult mentors. They engaged in complicated coping strategies and demonstrated a capacity for decision-making that displayed maturity beyond what would be expected for their age group. These findings led to specific recommendations for theory, research, and clinical practice in the area of the adolescent experience of HD. The research underscores the need for healthcare professionals to re-evaluate their view of adolescent autonomy and capacity for decision-making. / Graduate and Postdoctoral Studies / Graduate

The increasing transparence of the human genome has profound implications for how we understand health and illness and perceive our biological and social relatedness to others. Presymptomatic testing for adult onset conditions, in particular, creates the novel situation in which some individuals know in advance of impending illness while others learn that they have escaped such a fate. How families at risk for one adult onset condition — Huntington Disease (HD) — communicate about such information is the topic of this dissertation. HD is often described as a 'genetic time bomb'. It is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. There is no effective prevention or cure but with the advent of predictive testing in 1987 it became possible for at risk individuals to learn if they had inherited the mutation associated with HL\ Empirical studies on predictive testing for HD focus primarily on the individual psychological impacts of the test; few studies consider how families understand and attempt to manage genetic information in their everyday lives. This dissertation begins to address these lacunae by examining the stories that test candidates and their families tell about hereditary risk and predictive testing. These stories derive from a prospectively designed study which includes 102 in-depth, at-home interviews conducted in the pre and post-results period with 16 test candidates and 33 family members. Focusing on three narrative 'moments', the dissertation explores how study participants storied their experiences of: 1) learning about the family history of HD, 2) deciding to request the predictive test and, 3) making sense of an informative result. Drawing upon a social constructionist approach, the analysis emphasizes the processual nature of predictive testing as well as the significance of interpersonal communication in producing and reproducing the social realities in which genetic information acquires a particular salience. Given the recent proliferation of genetic tests as well as the absence of an adequate popular discourse on embodied risk, the research underscores lay actors' abilities to reframe existing clinical schema in order to interpret and manage hereditary risk in an intersubjectively meaningful way.

The increasing transparence of the human genome has profound implications for how we understand health and illness and perceive our biological and social relatedness to others. Presymptomatic testing for adult onset conditions, in particular, creates the novel situation in which some individuals know in advance of impending illness while others learn that they have escaped such a fate. How families at risk for one adult onset condition — Huntington Disease (HD) — communicate about such information is the topic of this dissertation. HD is often described as a 'genetic time bomb'. It is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. There is no effective prevention or cure but with the advent of predictive testing in 1987 it became possible for at risk individuals to learn if they had inherited the mutation associated with HL\ Empirical studies on predictive testing for HD focus primarily on the individual psychological impacts of the test; few studies consider how families understand and attempt to manage genetic information in their everyday lives. This dissertation begins to address these lacunae by examining the stories that test candidates and their families tell about hereditary risk and predictive testing. These stories derive from a prospectively designed study which includes 102 in-depth, at-home interviews conducted in the pre and post-results period with 16 test candidates and 33 family members. Focusing on three narrative 'moments', the dissertation explores how study participants storied their experiences of: 1) learning about the family history of HD, 2) deciding to request the predictive test and, 3) making sense of an informative result. Drawing upon a social constructionist approach, the analysis emphasizes the processual nature of predictive testing as well as the significance of interpersonal communication in producing and reproducing the social realities in which genetic information acquires a particular salience. Given the recent proliferation of genetic tests as well as the absence of an adequate popular discourse on embodied risk, the research underscores lay actors' abilities to reframe existing clinical schema in order to interpret and manage hereditary risk in an intersubjectively meaningful way. / Arts, Faculty of / Anthropology, Department of / Graduate