Stephen E. Farinelli

Induction of CPP32-like Activity in PC12 Cells by Withdrawal of Trophic Support DISSOCIATION FROM APOPTOSIS

Inhibitors of interleukin-1β converting enzyme (ICE) and a related group of cysteine aspartases of the ICE/ced-3 family inhibit cell death in a variety of settings, including in PC12 cells and sympathetic neurons following withdrawal of trophic support. To assess the particular member(s) of the ICE/ced-3 family that are relevant to cell death and to position their activation within the apoptotic pathway, we have used specific substrates to measure ICE-like and CPP32-like enzymatic activity in naive and neuronally differentiated PC12 cells that had been deprived of trophic support (nerve growth factor and/or serum). Rapid induction of CPP32-like, but not ICE-like, activity was observed. c-Jun kinase activation and the action of bcl-2 and other survival agents, such as cell cycle blockers, a NO generator, N-acetylcysteine, aurintricarboxylic acid, and actinomycin D occurred at a point further upstream in the apoptotic pathway compared with the aspartase activation. In living cells, zVAD-FMK, a pseudosubstrate aspartase inhibitor, blocked the activity/activation of the aspartase at concentrations about one order of magnitude lower than those required to promote survival, raising the possibility that the CPP32-like aspartase is not the main death effector in this model.

On the Mechanisms by Which Neurotrophic Factors Regulate Neuronal Survival and Cell Death

Publisher Summary Neuronal cell death is a naturally occurring component of the orderly ontogeny of the nervous system. Approximately half of all neurons born ultimately die during development. Access to limiting amounts of target-derived trophic factors, the paradigmatic example of which is nerve growth factor, appears to be a major element in the regulation of this process. Unfortunately, the death of neurons is not limited to perinatal periods. Even in the adult, experimental intervention or injury that interferes with neuronal-target interactions and consequent supply of trophic support can result in neuronal loss. Neuronal death also occurs in a variety of well-described neurodegenerative disorders of which Alzheimers disease, amyotrophic lateral sclerosis, and Parkinsonism are notable examples. There has been speculation that such disorders may involve specific components of the trophic factor supply or response mechanism and/or that trophic factors may be useful as ameliorative agents. This chapter reviews and draws somewhat speculative conclusions about recent work on the mechanisms by which neuronal cells are maintained by trophic factors and by which they die when such support is withdrawn.