Tabrizi, Sarah Joanna; (2000) Mitochondrial dysfunction in the pathogenesis of neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mitochondrial respiratory chain (MRC) dysfunction has been implicated in a wide variety of neurodegenerative diseases including Leber's hereditary optic neuropathy (LHON), Parkinson's disease (PD), Huntington's disease (HD) and dystonia. The underlying causes of the MRC dysfunction are heterogenous and may be a consequence of primary mtDNA or nuclear mutations, secondary to the underlying disease process or the effects of endogenous toxins. Cybrids have been used to investigate the interactions between the mitochondrial and nuclear genomes, and their effects on MRC dysfunction in LHON and dystonia. Although primary mutations in mitochondrial DNA complex I genes have been identified in LHON, other factors are thought to influence disease expression. While the complex I defect was maintained in the 3460 LHON/206 p° cybrids, it was absent in the 3460 LHON/A549 p° cybrids suggesting the nuclear environment influences the expression of the complex I defect in these 3460 LHON patients and that nuclear factors may contribute to the clinical phenotype. The complex I defect in focal dystonia was not transferred to either mixed or clonal focal dystonia platelet/ A549 p° cybrids lines suggesting it is caused by either a nuclear mutation or a toxin and excludes a mtDNA mutation. The previously reported severe deficiencies of mitochondrial complexes II/III and IV in HD caudate were also seen in HD putamen, and a decrease in aconitase activity was found to parallel the anatomic distribution of HD pathology. In the R6/2 transgenic mouse model of HD there were significant reductions in aconitase and complex IV activities in striatum. The relative sensitivity of complexes II/III and aconitase activity to nitric oxide and the increased immunostaining for inducible nitric oxide synthase and nitrotyrosine in the R6/2 brain supports the hypothesis that defective energy metabolism, excitotoxicity and NO contribute to pathogenesis in HD. Stable inducible cell models of HD and PD have been constructed using mutant and wild-type N-termini of huntingtin, and mutant G209A and wild-type α-synuclein respectively, to facilitate the investigation of the pathophysiology of MRC dysfunction in these disorders.

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