title: Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death.
abstract: Persistent protein synthesis inhibition (PSI) is a robust predictor of eventual neuronal death following cerebral ischemia. We thus tested the hypothesis that persistent PSI inhibition and neuronal death are causally linked. Neuronal viability strongly correlated with both protein synthesis and levels of eukaryotic (translation) initiation factor 4G1 (eIF4G1). We determined that in vitro ischemia activated calpain, which degraded eIF4G1. Overexpression of the calpain inhibitor calpastatin or eIF4G1 resulted in increased protein synthesis and increased neuronal viability compared with controls. The neuroprotective effect of eIF4G1 overexpression was due to restoration of cap-dependent protein synthesis, as well as protein synthesis-independent mechanisms, as inhibition of protein synthesis with cycloheximide did not completely prevent the protective effect of eIF4G1 overexpression. In contrast, shRNA-mediated silencing of eIF4G1 exacerbated ischemia-induced neuronal injury, suggesting eIF4G1 is necessary for maintenance of neuronal viability. Finally, calpain inhibition following global ischemia in vivo blocked decreases in eIF4G1, facilitated protein synthesis, and increased neuronal viability in ischemia-vulnerable hippocampal CA1 neurons. Collectively, these data demonstrate that calpain-mediated degradation of a translation initiation factor, eIF4G1, is a cause of both persistent PSI and neuronal death.
authors: Geriatric Research, Educational, and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
authors: Peter S
authors: PS
authors: Vosler
authors: Yanqin
authors: Y
authors: Gao
authors: Christopher S
authors: CS
authors: Brennan
authors: Akiko
authors: A
authors: Yanagiya
authors: Yu
authors: Y
authors: Gan
authors: Guodong
authors: G
authors: Cao
authors: Feng
authors: F
authors: Zhang
authors: Simon J
authors: SJ
authors: Morley
authors: Nahum
authors: N
authors: Sonenberg
authors: Michael V L
authors: MV
authors: Bennett
authors: Jun
authors: J
authors: Chen
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death; D004789:Enzyme Activation; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D007511:Ischemia / Q000201:enzymology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors; D012315:RNA Caps; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D039603:Eukaryotic Initiation Factor-4G; D011500:Protein Synthesis Inhibitors; D012315:RNA Caps; D034741:RNA, Small Interfering; C569103:eIF4G1 protein, rat; D002154:Calpain