McCarthy, Mary-Jane; (1997) The involvement of caspases in programmed cell death of sympathetic neurons. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Apoptosis plays a key role in shaping the nervous system during development and is also implicated in a number of neurodegenerative diseases. There is increasing evidence that the caspase family of proteases play a central role in the execution phase of apoptosis. In order to study the involvement of caspases in neuronal cell death, this thesis examines effects of the viral caspase inhibitor p35 and peptide caspase inhibitors, on sympathetic neurons isolated from the superior cervical ganglion (SCG). In these neurons, apoptosis can be induced by the withdrawal of nerve growth factor (NGF) and also by the addition of the kinase inhibitor staurosporine. p35 has been shown to be a broad spectrum inhibitor of the caspase family and is demonstrated to promote survival of SCG neurons when apoptosis is induced either by the withdrawal of NGF or addition of staurosporine. A number of peptide caspase inhibitors were also found to effectively inhibit apoptosis induced by both stimuli and indicated that caspase-1-like and caspase-3-like proteases are activated during death in these cells. Biochemical analysis of apoptotic SCG neurons demonstrated activation of caspase-3 following NGF withdrawal which was prevented by treatment with the cell permeable inhibitor benzyloxycarbonyl-Val-Ala-Asp (O-methyl)- fluoromethylketone (zVAD-fmk). In addition, p35 and zVAD-fmk inhibited a number of the morphological features associated with apoptosis, such as nuclear condensation, TUNEL labelling, and externalisation of phosphatidylserine.

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