Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.647197
Title: Investigation of the role of Parkinson's disease-associated proteins in mitochondrial homeostasis
Author: Delgado Camprubí, M.
ISNI:       0000 0004 5365 7188
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Abstract:
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Although most cases of PD are sporadic, 5-­‐10% are genetically inherited. The identification of genes associated with PD has enabled the dissection of molecular pathways implicated in the pathogenesis of the disease. A number of these genes encode mitochondrial proteins or proteins with a function in mitochondrial quality control, responsible for maintaining mitochondrial integrity and cellular homeostasis. Disease-­‐ associated mutations have shown to disrupt their protective function, associating mitochondrial dysfunction to the pathogenesis of the familial and idiopathic forms of the disease. This thesis investigates the function of PD-­‐associated proteins in mitochondrial quality control and how disease-­‐associated mutations contribute to mitochondrial dysfunction. Biochemical and live imaging techniques were used to assess the protective role of HtrA2 in mitochondria. Similar approaches were applied to investigate the effect of other PD-­‐ associated proteins on mitochondrial maintenance, and in particular, the mitochondrial localisation and function of Fbxo7. Results from this study revealed that upon activation of the p38-­‐cell-­‐stress pathway, phosphorylation of HtrA2 by CDK5 mediates a mitochondrial stress-­‐response necessary to maintain mitochondrial function. Fbxo7 was shown to translocate to mitochondria and, together with PINK1 and Parkin, mediate the selective autophagic clearance of depolarised mitochondria. Fbxo7 was shown to play a role in maintaining mitochondrial metabolism, as Fbxo7 deficient cells exhibit complex I deficiency combined with reduced maximal respiratory capacity and ATP content. PARP inhibitor restored respiration driven through complex I, suggesting that metabolic defects in Fbxo7 deficient cells are caused by PARP overactivation. Fibroblasts from PD patients carrying mutations on Vps35 or DJ-­‐1 exhibit increased Mfn1/2 levels, suggesting a possible effect on regulating Mfn expression and/or degradation. These results contribute to our understanding of the mitochondrial role of PD-­‐related proteins and help to explain why defective quality control mechanisms lead to mitochondrial dysfunction in PD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.647197  DOI: Not available
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