Krige, David;
(1994)
Mitochondrial abnormalities in Parkinson's disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The cause of neurodegeneration in the substantia nigra of the brains of Parkinson's disease (PD) patients remains unknown. The presence of a defect of NADH CoQ1 reductase (complex I of the mitochondrial respiratory chain) in the disease is now well established, although its relevance to disease pathogenesis is unknown. The tissue specificity of the defect is contentious, and was therefore investigated in PD platelets. Complex I activity measured in PD whole platelet homogenates was normal. However when a platelet mitochondrially- enriched fraction (MEF) was prepared, and the complex I assay was modified to maximise activity in platelet MEFs, a slight (16%), but statistically significant decrease in mean complex I activity in PD samples was detected. The molecular basis of the complex I enzymatic defect in PD is unknown. To determine the presence of any defect in the complex I protein, the structure and subunit composition of the complex in the PD substantia nigra was investigated by two methods; immunoprecipitation of the complex using antibodies raised to the holoenzyme, followed by denaturing electrophoresis and silver staining of the polypeptides; and quantitation of the concentration of the complex by ELISA (enzyme-linked immunosorbent assay), using affinity-purified antibodies to the complex I holoenzyme and to specific complex I subunits. By immunoprecipitation, no major differences were detected between complex I from PD and control substantia nigra. However, by ELISA it was shown that PD substantia nigra samples with low complex I enzymatic activity (40% less than controls) contained low concentrations of complex I protein (40% less than controls). To explore the possibility that the complex I defect in PD is caused by a defect in the detoxification process of a putative complex I inhibitor, experiments were initiated to correlate complex I activity in the PD substantia nigra with the presence of mutations in the cytochrome P450 debrisoquine hydroxylase gene (CYP2D6). Due to the limited sample number, no samples contained homozygous recessive mutations which would affect the debrisoquine metaboliser phenotype.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Mitochondrial abnormalities in Parkinson's disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10098896 |
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