title: Mechanisms underlying suppression of protein synthesis induced by transient focal cerebral ischemia in mouse brain.
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 eIF2alpha kinase PERK. In this study, we investigated ischemia-induced changes in protein levels and phosphorylation states of the initiation factors eIF2alpha, eIF2B epsilon, 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. eIF2alpha was transiently phosphorylated after ischemia, peaking at 1-3 h of recovery. eIF2B epsilon and p70 S6 kinase were completely dephosphorylated during ischemia and phosphorylation did not recover completely following reperfusion. In addition, eIF2B epsilon, 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 eIF2B epsilon and p70 S6K starting during ischemia, a transient phosphorylation of eIF2alpha during early reperfusion, and a marked decrease of eIF2B epsilon, 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.
authors.affiliation: Department of Experimental Neurology, Max-Planck-Institute for Neurological Research, 50931, Köln, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mengesdorf
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.forename: Günter
authors.initials: G
authors.lastname: Mies
authors.forename: Wulf
authors.initials: W
authors.lastname: Paschen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D039603:Eukaryotic Initiation Factor-4G; D007527:Isoenzymes; D021122:Protein Subunits; D011506:Proteins; D019284:Thapsigargin; D038762:Ribosomal Protein S6 Kinases, 70-kDa