Role of extracellular signal regulated kinases in neuronal death and survival

Abstract

The death of neurons is one of the forces that shapes the development of the nervous system. Most neurons in the mature nervous system are postmitotic cells and therefore cannot be easily replaced by cell renewal. Thus, the number of mature neurons in the nervous system is primarily dependent on the extent of neuronal survival and can decline when cell death is induced by damaging insults. Excessive neuronal death underlies the loss of nerve cells and the subsequent functional decline observed in several major neurological diseases including stroke or dementia. As neuronal death and/or survival are greatly affected by the cellular environment, it is expected that signal transduction pathways activated by extracellular or intracellular signals will regulate these processes. Extracellular signal regulated kinases (ERKs) that belong to the mitogen activated protein kinase (MAP kinase) family are important carriers for multiple informational inputs that reach the neuron. For instance, they play a critical role in neuronal plasticity, which is a substrate for learning and memory. The purpose of this minireview series is to discuss the literature on the involvement of ERKs in the regulation of neuronal survival and/or neuronal death. In the first paper of the series, Hetman & Gozdz present evidence supporting the role of ERK½ in the suppression of neuronal death and/or the enhancement of neuronal survival. It appears that ERKI/2 may transduce the prosurvival activity of several protective extracellular stimuli. ERK½ may also be involved in mobilizing a defensive response in neurons exposed to damage. In the second paper, Cavanaugh reviews reports indicating that ERK5 may play an important role in protection against neuronal death. It seems that this kinase serves as a prosurvival transducer in immature neurons during development, and that the prosurvival activity of ERK5 involves regulation of gene expression. Finally, Chu et al. present literature indicating that in several cases, activation of ERKI/2 may transduce toxic signals that trigger neuronal death. Indeed, the chronic activation of ERK½ in certain cellular compartments may contribute to the neurodegenerative cascades that are involved in Alzheimer's or Parkinson's diseases as well as in ischemic stroke. It appears that there are several questions concerning ERKs involvement in the regulation of neuronal death/ survival that will require further study. They include the following: (a) what are the target mechanisms that mediate ERKs effects on neuronal death/survival? and (b) which factors can determine the outcome of ERKs activity on neuronal death/survival? Addressing these questions may aid the development of neuroprotective interventions that will target signaling via ERKs.