Mechanisms underlying suppression of protein synthesis induced by transient focal cerebral ischemia in mouse brain

Thorsten Mengesdorf, Christopher G. Proud, Günter Mies, Wulf Paschen

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Transient global cerebral ischemia triggers suppression of the initiation step of protein synthesis, a process which is controlled by endoplasmic reticulum (ER) function. ER function has been shown to be disturbed after transient cerebral ischemia, as indicated by an activation of the ER-resident eIF2α kinase PERK. In this study, we investigated ischemia-induced changes in protein levels and phosphorylation states of the initiation factors eIF2α, eIF2Bε, and eIF4G1 and of p70 S6 kinase, proteins playing a central role in the control of the initiation of translation. Transient focal cerebral ischemia was induced in mice by occlusion of the left middle cerebral artery. Transient ischemia caused a long-lasting suppression of global protein synthesis. eIF2α was transiently phosphorylated after ischemia, peaking at 1-3 h of recovery. eIF2Bε and p70 S6 kinase were completely dephosphorylated during ischemia and phosphorylation did not recover completely following reperfusion. In addition, eIF2Bε, eIF4G1, and p70 S6 kinase protein levels decreased progressively with increasing recirculation time. Thus, several different processes contributed to ischemia-induced suppression of the initiation of protein synthesis: a long-lasting dephosphorylation of eIF2Bε and p70 S6K starting during ischemia, a transient phosphorylation of eIF2α during early reperfusion, and a marked decrease of eIF2Bε, eIF4G1, and p70 S6K protein levels starting during vascular occlusion (eIF4G1). Study of the mechanisms underlying ischemia-induced suppression of the initiation step of translation will help to elucidate the role of protein synthesis inhibition in the development of neuronal cell injury triggered by transient cerebral ischemia.

Original languageEnglish
Pages (from-to)538-546
Number of pages9
JournalExperimental Neurology
Volume177
Issue number2
DOIs
Publication statusPublished - 1 Jan 2002
Externally publishedYes

Keywords

  • Endoplasmic reticulum
  • Initiation factors
  • Mouse brain
  • Phosphorylation
  • Protein synthesis
  • Stress response
  • Transient focal cerebral ischemia

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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