The discovery of the genetic basis of neurodegenerative disorders has enabled the generation of models to study their pathogenesis. In part one, human embryonic kidney cells with inducible expression of wild-type or mutant G209A cc-synuclein modelled increased a-synuclein expression and a familial form of Parkinson's disease, respectively. Both wild-type and mutant a- synuclein were localised to vesicles, some of which were catecholaminergic. Over- expression of wild-type or mutant (G209A) a-synuclein alone did not reduce cell viability, cause oxidative stress or impair mitochondrial function. However, mutant a- synuclein expression enhanced the susceptibility to dopamine toxicity causing increased oxidative stress and cell death. This effect was similar to that of reserpine, an inhibitor of vesicular monoamine uptake, in controls. These results suggest that a-synuclein may play a role in dopamine compartmentalisation. Loss of function conferred by the G209A mutation could therefore increase cytoplasmic dopamine concentrations with subsequent cell damage or death. In part two, myoblast cell lines were established, and characterised, from the R6/2 mouse model of Huntington's disease (HD). Mutant N-terminal huntingtin transgene over-expression was associated with significantly greater numbers of myotubes suggesting a role of huntingtin in muscle differentiation. In long-term culture, differentiated R6/2 myotubes, but not controls, formed nuclear huntingtin inclusions. Inclusion number depended upon culture medium conditions suggesting that environmental factors might be relevant. This model of HD in non-neuronal post mitotic cells may be useful to study the pathophysiology of, and possibly the effect of therapeutics on, huntingtin aggregate formation. The third part examined the suggestion that codon 129 homozygosity of the prion protein (PrP) gene may predispose to sporadic inclusion body myositis (sIBM). Codon 129 zygosity in 41 sIBM muscle biopsies was not significantly different to results published in population studies in several Western countries suggesting sIBM is not linked to homozygosity at codon 129 of the PrP gene.

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Research studies exploring outcomes in people with Huntington's disease (HD) suggest that distress is common in this group. Nonetheless, there is little research investigating psychological factors which contribute to distress in people with HD. The present thesis therefore considers aspects relating to the psychological outcomes of anxiety and depression for people with HD, using the self-regulation model (SRM) as a biopsychosocial framework to develop understanding of the individuals' experience. Section one comprises a narrative review which advocates for the use of the SRM for this population and considers research studies in support of this argument. The review considers each of the illness perceptions in light of psychological distress and further explores the role of coping in this process. Moreover, suggestions are made in relation to further research which would enhance the applicability of the SRM for researchers and clinicians. In section two, a research paper reports the findings of a quantitative study which used hierarchical multiple regression to explore the relationship between the domains of the SRM and psychological distress in 87 adults with a diagnosis ofHD. The findings of this study indicate that illness perceptions relating to the SRM reflect distinct and meaningful constructs for people with a diagnosis of HD. Furthermore, the Illness Perceptions Questionnaire-Revised (IPQ-R) demonstrated satisfactory internal consistency and test-retest reliability when adapted for HD. The findings are discussed in relation to existing research and clinical implications are proposed. Interventions such as acceptance and commitment therapy and solution-focused interventions are considered as useful approaches for people with HD. Moreover, the current study provides further evidence for a collaborative approach to the treatment ofHD. The final section, section 3, contains a further discussion of the findings, as well as personal reflections and recommendations for future research.

Background: People with Huntington’s disease (HD) can be affected by motor, cognitive and behavioural symptoms. The length of the illness trajectory can result in patients receiving care at home for extended periods during which the contribution from family caregivers is invaluable. There has been little research into patient or carer perspectives on needs or how these should be met, and how these correspond to professional viewpoints. Objectives: To gain an understanding of living with, caring for and working in the field of HD. Study design: A collective case study approach was used to gather data from the person with HD, their family carer and a nominated healthcare professional to build 15 cases involving 33 individuals and 115 interactions (68 interviews and 47 observations) over three years of study participation. Findings: Living with HD requires continued readjustment to maintain balance between increasing disability, diminishing cognition and living well at home. Patients and carers were challenged to cope with: the diagnosis; an impulse to secrecy and a duty to share knowledge; autonomy and decision making; the transformation of homes to hospitals; and a shift in the burden of care when the patient moved to a residential care home. Examination of services showed how multidisciplinary working, a keyworker approach, disease, person and service specific knowledge alongside continuity of staffing contribute to quality care. Conclusion: This is the first qualitative study of living with HD incorporating multiple perspectives over time. It explored the complexity of living with HD and the ways in which care can be provided in the community. The study identified a number of daily challenges for both family and professional carers when changes in capacity occur slowly over time. Holistic, multidisciplinary and flexible care is shown to be essential for those trying to balance the delicate equilibrium of living with HD. nb. The journal articles and book extracts in appendix A have not been included in the electronic version for copyright reasons.

Histone deacetylase (HDAC) inhibitors (HDACIs) have long been studied and shown promises in the treatment of various neurodegenerative disorders including Huntington’s disease (HD). Based on many demonstrated potentials of HDACIs in mitigating various diseases, we evaluated the utility of [18F]FAHA, a radiolabeled derivative of suberoylanilide hydroxamic acid (SAHA), as a PET imaging agent for characterizing HDAC activity in a non-human primate model and a R6/2 transgenic mouse model of HD. We were aiming at HD as a potential first application, and therefore also examined the expression of HDAC and acetyl histone (AH) in brains of HD patients. This thesis describes that [18F]FAHA was metabolized rapidly to [18F]FACE in both blood plasma and brain. Kinetic analysis indicated that peripherally generated [18F]FACE contributed to the total brain activity. We therefore used a dual-input function model to analyze the kinetics of tracer accumulation and inhibition by SAHA in rhesus monkeys. Parametric images demonstrated the inhibition of HDAC activity in the brain by SAHA in a dose-dependent manner. Huntington’s mice (R6/2) showed a gradual increase of [18F]FAHA accumulation in all organs including the brain with age. In human tissue we found significant losses of acetyl histons expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD, while the level of HDAC 5 was increased in these cells. The data obtained in rhesus monkeys indicated that PET imaging with [18F]FAHA could be used as a pharmacodynamic biomarker of the inhibition of class IIa HDACs by HDACIs in the brain and facilitate the development and clinical translation of novel class-IIa HDACIs.