Neuronal Cell Death

The study of the mechanisms of cell death proceeds at an impressive pace. Here, our aim is to provide an overview of recent developments for neurobiologists not directly involved in the cell death field. Although programmed cell death also affects other cell types in the nervous system, we have focused specifically on neurons. We summarize significant advances over the last two years, and ask to what extent it is now possible to determine: (1) why a given neuron dies at a given moment, (2) how it dies as a result of different stimuli, and (3) how it is protected from death in some circumstances. Neurons may die at many different developmental stages and for many different reasons. As in other tissues, different stimuli produce quite different morphological manifestations of cell death. Many authors have sought to distinguish apoptosis (involving nuclear and cytoplasmic condensation and intranucleosomal DNA cleavage, followed by phagocytosis) from necrosis (involving swelling of mitochondria and endoplasmic reticulum and subsequent loss of membrane integrity). However, these paradigms were developed for cancer cells (Wyllie et al., 1980), and may be only partially valid for analyzing cell death in the nervous system, as in some cases aspects of both may be manifest (reviewed by Clarke, 1998). Here, we will therefore use these terms only in their most general sense, to distinguish where necessary between processes that involve activation of dedicated cellular suicide machinery (programmed cell death, apoptosis) and the destruction of the cell by external insults, not necessarily involving the activation of an intracellular program (necrosis).