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Title: Investigation of the mitochondrial functions of proteins genetically associated with Parkinson's Disease
Author: Burchell, V. S.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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Parkinson’s disease (PD) is a common neurodegenerative disorder which usually occurs sporadically, but in 5-10% of cases is genetically inherited. Many of the causative mutations underlying these familial forms have been identified, and studying the functions of the proteins encoded by these genes has highlighted several common pathogenic mechanisms. In particular, mitochondrial dysfunction has been shown to play a major role in the pathogenesis of both familial and sporadic forms of the disease. This thesis investigates the importance of the proteins encoded by these PD-associated genes in mitochondrial function, focusing on two proteins in detail. Firstly, live cell imaging techniques were used to investigate the mitochondrial physiology of cells derived from HtrA2 knockout mice, an animal model in which the loss of a mitochondrial protein gives rise to severe neurodegenerative phenotype. Similar approaches were then applied to an RNAi screen to investigate the effects of other PD-associated genes on mitochondrial function, while a separate study specifically investigated the putative mitochondrial localisation and function of the PD-associated protein Fbxo7. Results from these studies revealed that HtrA2 has an important role in maintaining the function of the ATP synthase, as HtrA2 deficient cells exhibited a severe uncoupling combined with an increase in proton translocation through the ATP synthase but a reduction in ATP synthesis. Furthermore, Fbxo7, a protein with no reported link to the mitochondria, was found to partially localise to the mitochondria under basal conditions and to further accumulate on depolarised mitochondria. Further work indicated that this protein interacts with two other PD proteins, PINK1 and Parkin, and together with these proteins functions in a previously described pathway to mediate the selective autophagic clearance of damaged mitochondria. These results contribute to our understanding of the functions of these proteins and further emphasise the relevance of mitochondrial dysfunction in PD pathogenesis.
Supervisor: Plun-Favreau, H. ; Wood, N. W. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available