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Mitochondrial Function, Oxidative Stress and Parkinson's Disease

Al Shahrani, Mesfer M.; (2018) Mitochondrial Function, Oxidative Stress and Parkinson's Disease. Doctoral thesis (Ph.D), UCL (University College London).

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The loss of the activity of mitochondrial respiratory chain (MRC) complexes, particularly complex I, has been implicated in Parkinson’s disease (PD) pathogenesis. However, it is still uncertain whether altered MRC activity is an early event in the pathophysiology of PD, or a late consequence of cellular stress. Therefore, this thesis contributes differently from other studies as to the ongoing investigations about MRC activity in PD post-mortem brain based on pathological severity. This study demonstrates that loss of complex I activity occurs in regions with both moderate and mild pathology in PD brain. Furthermore, multiple complex defects were noted in the moderate pathology region. However, the activity of complex II which is entirely encoded by nuclear DNA appeared to be preserved. The exact mechanism of multiple complex defects remain elusive. However, the possibility arises that impairment of complex I results in secondary damage to the other complexes. Here, neuroblastoma cells were employed to study the effect of pharmacologically induced MRC complex I deficiency upon the activity of the other complexes. In this model, rotenone-treated (100 nM; 24-48 hours) SH-SY5Y cells induced an inhibition of complex I. At 24 hours no effect was observed on the other complexes. However at 48 hours, multiple complex defects were noted, but the activity of complex II appeared to be preserved. Additionally, bioenergetics and glutathione status were compromised. By utilizing this model, the effectiveness of antioxidants in alleviating the progression of complex I deficiency on other complexes were also evaluated. Furthermore, the use of the Oxygraph-2K® instrument together with a step-wise protocol was developed to assess the integrated mitochondrial function in cultured SH-SY5Y cells. Additionally, the focus of attention was also to validate the fibroblast growth factor-21 ELISA assay. Based on the results, this assay appears to be a useful as a biomarker for mitochondrial dysfunction.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mitochondrial Function, Oxidative Stress and Parkinson's Disease
Event: UCL
Language: English
Additional information: Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. - Third party copyright material has been removed from this e-thesis.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10064465
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