Skipper, Lisa Marie;
(2005)
Parkinson's disease susceptibility: Genetic mapping in an isolated population.
Doctoral thesis , UCL (University College London).
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Abstract
Parkinson's disease (PD) is an aetiologically complex, progressive and debilitating neurodegenerative disorder that primarily affects the elderly population. It is characterised clinically by the presence of motor symptoms including resting tremor, bradykinesia and rigidity; pathologically by neuronal loss within mid brain regions and intraneuronal inclusions comprising numerous protein aggregates. Disease risk factors are both environmental and genetic. To date, at least 10 genetic loci are implicated and specific mutations have been identified in SNCA, PRKN, UCH-Ll, DJ-1 and PINKL Variability within the MAPT gene has also been associated with disease risk. Population isolates are a powerful tool for the dissection of genetically complex disorders, due to expected genetic homogeneity and linkage disequilibrium (LD) levels. This project has focused upon a population isolate from Trondheim, central Norway, in which most individuals with PD show no family history of disease. In the first study of the genetic factors involved in PD within the Norwegian population, we chose to investigate recessive (PARK2, PARK6 and PARK7) and susceptibility (MAPT and PARK 10) loci, which may manifest as sporadic disease. Analysis of PRKN (PARK2) suggested that this locus contributes to PD in the Norwegian population and that the high frequency of the A82E mutation in the Trondheim community is due to a founder effect. In addition, a novel proline insertion mutation was identified. Detailed examination of the MAPT H1 haplotype associated with parkinsonism, showed that 'H1' consists of a group of related but distinct haplotypes, one of which is preferentially associated with PD. The variability most associated with disease was shown to lie at the 5' end of MAPT, encompassing exons 1 to 4. Candidate gene analysis and novel multipoint LD mapping methods at PARK10 identified two genes, EPS15 and NRDl, which may also contribute to PD risk. Further molecular genetic analysis will contribute to the understanding of pathogenic mechanisms through the use of cellular and animal models, and ultimately the development of both palliative and preventative therapies.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Parkinson's disease susceptibility: Genetic mapping in an isolated population |
| Identifier: | PQ ETD:602603 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1446678 |
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