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Title: The role of caspases in the death of sympathetic neurons
Author: Fletcher, G. C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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Primary neurons from the rat superior cervical ganglion (SCG) are dependent on nerve growth factor (NGF) for their survival both in vivo and in vitro and die by apoptosis after NGF withdrawal. This study examines the involvement of caspases in SCG neuronal death and the circumstances under which caspase inhibitors both prevent apoptosis and allow the functional recovery of SCG neurons. Firstly, the effects of three caspase inhibitors on NGF-deprivation-induced apoptosis were tested. The most effective inhibitor at non-toxic concentrations was BOC-aspartyl(O-methyl) fluoromethylketone (BAF), which was further characterised in assays examining caspase activity during SCG neuronal apoptosis. The long-term survival of cells in which BAF treatment had prevented apoptosis was followed and it was found that newly-isolated cells could not survive after the readdition of NGF, in contrast to established neuronal cultures. The reasons to account for the lack of long-term survival of the newly-isolated NGF-deprived, BAF-treated neurons were examined. The most striking observation was the increased autophagic activity at the time of NGF addition and the selective loss of mitochondria three days later. Thus, newly-isolated cultures appear to become committed to death as a result of mitochondrial damage upstream of caspase activation. In contrast established neuronal cultures, which were rescued after caspase inhibition had prevented apoptosis, appear to become committed to death coincident with caspase activation. The data presented here suggest that the mechanism that commits neurons to die must be established before it can be predicted whether survival factors can rescue neurons when death has been prevented by caspase inhibition.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available