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Molecular study of cell culture models of Parkinson's disease and Huntington's disease.

Orth, M.; (2005) Molecular study of cell culture models of Parkinson's disease and Huntington's disease. Doctoral thesis , University of London. Green open access

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The discovery of the genetic basis of neurodegenerative disorders has enabled the generation of models to study their pathogenesis. In part one, human embryonic kidney cells with inducible expression of wild-type or mutant G209A cc-synuclein modelled increased a-synuclein expression and a familial form of Parkinson's disease, respectively. Both wild-type and mutant a- synuclein were localised to vesicles, some of which were catecholaminergic. Over- expression of wild-type or mutant (G209A) a-synuclein alone did not reduce cell viability, cause oxidative stress or impair mitochondrial function. However, mutant a- synuclein expression enhanced the susceptibility to dopamine toxicity causing increased oxidative stress and cell death. This effect was similar to that of reserpine, an inhibitor of vesicular monoamine uptake, in controls. These results suggest that a-synuclein may play a role in dopamine compartmentalisation. Loss of function conferred by the G209A mutation could therefore increase cytoplasmic dopamine concentrations with subsequent cell damage or death. In part two, myoblast cell lines were established, and characterised, from the R6/2 mouse model of Huntington's disease (HD). Mutant N-terminal huntingtin transgene over-expression was associated with significantly greater numbers of myotubes suggesting a role of huntingtin in muscle differentiation. In long-term culture, differentiated R6/2 myotubes, but not controls, formed nuclear huntingtin inclusions. Inclusion number depended upon culture medium conditions suggesting that environmental factors might be relevant. This model of HD in non-neuronal post mitotic cells may be useful to study the pathophysiology of, and possibly the effect of therapeutics on, huntingtin aggregate formation. The third part examined the suggestion that codon 129 homozygosity of the prion protein (PrP) gene may predispose to sporadic inclusion body myositis (sIBM). Codon 129 zygosity in 41 sIBM muscle biopsies was not significantly different to results published in population studies in several Western countries suggesting sIBM is not linked to homozygosity at codon 129 of the PrP gene.

Type: Thesis (Doctoral)
Title: Molecular study of cell culture models of Parkinson's disease and Huntington's disease.
Identifier: PQ ETD:593085
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest Third party copyright material has been removed from the e-thesis.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical Neuroscience
URI: https://discovery.ucl.ac.uk/id/eprint/1445761
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