Cell cycle related signaling in neuronal death

Evidence indicates that neuronal loss in the course of neurodegenerative disease often occurs through programmed death processes. The development of effective therapeutic treatments for such diseases requires detailed knowledge of the intracellular signaling pathways controlling these death processes. Previous work has identified cyclin-dependent kinases, a family of kinases normally involved in the control of cell division, as potential regulators of death in neurons. For instance, a number of events that occur during the G1 to S transition in proliferating cells, such as cyclin D/cdk4 activation and phosphorylation of its target, pRb, have been detected in dying neurons and appear to be essential for death. In the cell cycle, pRb phosphorylation is followed by activation of the transcription factor E2F1. It is not known if E2F1 is also involved in neuronal death. I found that E2F1 expression in neurons induced apoptotic death dependent on Bax but independent of p53. Also, E2F1 mRNA and protein levels increase in neurons induced to die by exposure to low concentrations of K+, and neurons from E2F1 null mice are resistant to this death. These results are consistent with participation of endogenous E2F1 in neuronal death signaling. Cdk5 is a member of the cyclin-dependent kinase family which does not have a function in the cell cycle. Instead cdk5, together with its binding partners p35 and p39, is involved in a variety of neuronal functions. Cleavage of p35 into a smaller p25 form has been shown to convert cdk5 into a death promoting kinase. However, it is not yet clear under which circumstances cdk5 signals death, and there is also some contrasting evidence suggesting cdk5 is a pro-survival factor. By targeting dominant negative cdk5 expression to either the nuclear or cytoplasmic compartments I show that cdk5 performs a pro-death function within the nucleus but a pro-survival function within the cytoplasm. The nuclear pro-death signal is relevant only when p25 is produced early, as it is following glutamate induced death, and not when it is produced late as a result of caspase activation, as it is following DNA damage