Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489728
Title: The role of genetic risk factors on the phenotype of Parkinson's Disease
Author: Clark, Graeme Richard
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2008
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Abstract:
Parkinson's disease (PD) is the second most comInon neurodegenerative disease after Alzheimer's disease (AD), and effects approximately 1% of the over 50 population. PD can be clinically characterised by the so called 'cardinal features', which include resting tremor rigidity, bradykinesia and postural instability. Many PD patients later develop non-motor symptoms, including depression, psychosis, anxiety, insomnia and dementia. Previous studies have focussed on dementia in PD, with co-prevalence rates of between 10-80% being reported, the most consistent estimates being 25-30%. Also, PD patients have been shown to be around five times more likely to develop dementia than control subjects. It is also widely believed that PD and AD may share a common detrimental pathway. In recent years, studies have shown and association between a variety of genes and genetic risk factors, with the progression of cognitive decline in PD patients. Therefore this study will further investigate genetic risk factors which may modulate the dementia phenotype of PD. The main focus of this thesis is the effect of potential susceptibility genes on the phenotype ofPD patients. Initially, work was undertaken in order to assess the role of dementia susceptibility genes, and their interaction. This incorporated genotyping for the Microtubule associated protein tau (l'v1APT) risk haplotypes, the a-synuclein (SNCA) risk SNP (rs356219), the glycogen synthase kinase 3/3 (GSK3B) risk SNPs, and finally genotyping for Apolipoprotein E (ApoE). These genes were targeted for either their known role in PD (for example SNCA - a major component of Lewy bodies), for their known involvement in dementia in other neurodegenerative diseases (for example MAPT - in progressive supraneuclear palsy and corticobasal degeneration, ApoE e4 in Alzheimer's disease), or for their known interaction with dementia causing genes (for example GSK3B - involvement in MAPT phospohorylation). Our results suggest involvement of these genes, or their risk haplotypes, with the presence of dementia, but show variable interactions between them. Two further susceptibility genes were screened in order to determine their involvement in PD. Firstly, the SCAl7 gene (Tata-box binding protein -TBP) was shown to have a significant association with PD, through the presence of increased CAA/CAG repeats in PD patients. It should be noted that the range of repeats found in the PD group were of the upper limits of the normal repeat range. It was hypothesised that the TBP protein may accumulate in the LBs of individuals possessing larger CAG/CAA repeats, however immunohistochemical work showed no TBP protein localisation in the LBs. The initial association of TBP repeats could not be replicated in a larger Cambridge cohort. The final susceptibility gene screened in PD was the gene responsible for the lysosomal storage enzyme glucocerebrosidase (GBA). GBA gene mutations are responsible for Gaucher's Disease, whereby the protein structure is altered and results in abnormal lysosomal storage. A variety of clinical features are associated with GD, with particular interest shown in the development of Parkinsonism. Studies have shown the presence of GBA mutations in between 4-21% of PD with dementia and dementia with Lewy body's disease. In this thesis the entire sequencing region of the GBA gene was screened fur known and novel mutations in PDD and DLB cases. We found mutations to be present in approximately 6.6% of our patient group, with no mutations found in controls. These results suggest an association of GBA gene mutations and dementia in PD and DLB. The final element of this thesis was to evaluate the involvement of the LRRK2 6055G>A (G2019S) mutation in both idiopathic and familial PD. The LRPJ<2 (PARK8) gene is the most recent, and probably most exciting, monogenic cause identified for PD. It has been shown to be causative for 1-2% of idiopathic PD cases, and 6-7% offamilial PD of European origin. In this study, the aim was to replicate the findings of others, which showed a prevalence of the mutation in approximately 1% of idiopathic and 12% of familial PD cases. It has also been suggested that the G20l9S mutation in European subjects arose as the result of two separate founder events. We sought to elucidate these previous findings, and confirmed from the idiopathic and familial cases, that the mutation arose from at least two founder events. The data presented in this thesis highlights the heterogeneity of PD, and further demonstrates that it is a truly multifactorial range of disorders as opposed to a single disease entity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Newcastle University, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.489728  DOI: Not available
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