Suppression of protein synthesis after transient cerebral ischemia

Abstract

Transient cerebral ischemia is a severe form of stress inducing disturbances of various biochemical and molecular–biological pathways. A common feature of the responses of cells to a severe form of stress is down-regulation of translation. Ischemia-induced blocking of translation is reversible in resistant brain regions but irreversible in vulnerable structures. Suppression of protein synthesis is brought about by a blocking of translation at the initiation site, as indicated by phosphorylation of the eukaryotic initiation factor eIF2α and disaggregation of polyribosomes. During ischemia, initiation factors such as eIF2Bε, which are phosphorylated in the physiological state, become dephosphorylated. The phosphorylation state recovers slowly during reperfusion. However, this recovery is counterbalanced by degradation of the respective proteins. eIF4G starts to be degraded already during ischemia, and degradation is aggravated following reperfusion. Reperfusion induces a transient phosphorylation of eIF2α, a factor playing a central role in the control of the initiation step of protein synthesis. The prolonged suppression of translation induced by transient cerebral ischemia is likely to be due to a combination of events: phosphorylation of eIF2α during early reperfusion, dephosphorylation of eIF2Bε, and loss of eIF4G may all contribute to this pathological process.