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Effects of inhibitors of apoptotic pathways in Parkinson's disease models

Bilsland, James; (2003) Effects of inhibitors of apoptotic pathways in Parkinson's disease models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Dopaminergic cell death in models of Parkinson's disease has been extensively studied, but the mechanisms underlying the toxicity remain unclear. Some reports have indicated that the cell death is apoptotic and involve the caspase family of cysteine proteases; there is some controversy in the literature regarding this. The current study was undertaken to evaluate the mechanism of cell death and apoptotic pathways activated in the 1-methyl-4 phenlypyridinium (MPP+) model of dopaminergic cell death. A culture model for primary foetal rat mesencephalon was established and the presence of dopaminergic neurones validated. The role of the caspases was evaluated, using both commercially available and novel selective inhibitors of the caspase pathway. Immunocytochemical staining was used to visualise active caspase, and to evaluate apoptotic nuclear morphology. A similar approach was used to examine the role of the stress activated mitogen activated protein kinases c-jun-N-terminal kinase and p38. Novel selective inhibitors were used to block these pathways; and immunocytochemistry used to evaluate survival effects on dopaminergic neurones and on expression of phosphorylated c-jun. Finally, a model of in vivo dopaminergic cell death was established using the toxin 6- hydroxydopamine; the effects of toxin treatment on expression of phosphorylated c-jun in the nigra was evaluated. The results show that MPP+ induced apoptosis is mediated through caspases, especially caspase 3, and that inhibition of the JNK pathway but not the p38 pathway spares cells by inhibiting caspase 3 activation. In the in vivo studies it was shown that 6-OHDA causes nigral cell death and phosphorylation of c-jun.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Effects of inhibitors of apoptotic pathways in Parkinson's disease models
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Parkinson's disease
URI: https://discovery.ucl.ac.uk/id/eprint/10098501
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