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Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death
journal contribution
posted on 2023-06-08, 12:55 authored by Peter S Vosler, Yanqin Gao, Christopher S Brennan, Akiko Yanagiya, Yu Gan, Guodong Cao, Feng Zhang, Simon Morley, Nahum Sonenberg, Michael V L Bennett, Jun ChenPersistent 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.
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- Published
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- Published version
Journal
Proceedings of the National Academy of SciencesISSN
1091-6490Publisher
National Academy of SciencesExternal DOI
Issue
44Volume
108Page range
18102-18107Department affiliated with
- Biochemistry Publications
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- No
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- Yes
Legacy Posted Date
2012-10-31First Compliant Deposit (FCD) Date
2013-11-04Usage metrics
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