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Investigation of the role of Parkinson's disease-associated proteins in mitochondrial homeostasis

Delgado Camprubí, M; (2015) Investigation of the role of Parkinson's disease-associated proteins in mitochondrial homeostasis. Doctoral thesis , UCL (University College London).

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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.

Type: Thesis (Doctoral)
Title: Investigation of the role of Parkinson's disease-associated proteins in mitochondrial homeostasis
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: http://discovery.ucl.ac.uk/id/eprint/1460299
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