PERK is responsible for the increased phosphorylation of eIF2α and the severe inhibition of protein synthesis after transient global brain ischemia
Article first published online: 5 JUL 2005
Journal of Neurochemistry
Volume 94, Issue 5, pages 1235–1242, September 2005
How to Cite
Owen, C. R., Kumar, R., Zhang, P., McGrath, B. C., Cavener, D. R. and Krause, G. S. (2005), PERK is responsible for the increased phosphorylation of eIF2α and the severe inhibition of protein synthesis after transient global brain ischemia. Journal of Neurochemistry, 94: 1235–1242. doi: 10.1111/j.1471-4159.2005.03276.x
- Issue published online: 5 JUL 2005
- Article first published online: 5 JUL 2005
- Resubmitted manuscript received April 21, 2005; accepted April 25, 2005.
- eukaryotic initiation factor 2;
- RNA-dependent protein kinase-like endoplasmic reticulum kinase;
- transgenic mice;
- transient cerebral ischemia;
- translation initiation factors
Reperfusion after global brain ischemia results initially in a widespread suppression of protein synthesis in neurons that is due to inhibition of translation initiation as a result of the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). To address the role of the eIF2α kinase RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) in the reperfused brain, transgenic mice with a targeted disruption of the Perk gene were subjected to 20 min of forebrain ischemia followed by 10 min of reperfusion. In wild-type mice, phosphorylated eIF2α was detected in the non-ischemic brain and its levels were elevated threefold after 10 min of reperfusion. Conversely, there was no phosphorylated eIF2α detected in the non-ischemic transgenic mice and there was no sizeable rise in phosphorylated eIF2α levels in the forebrain after ischemia and reperfusion. Moreover, there was a substantial rescue of protein translation in the reperfused transgenic mice. Neither group showed any change in total eIF2α, phosphorylated eukaryotic elongation factor 2 or total eukaryotic elongation factor 2 levels. These data demonstrate that PERK is responsible for the large increase in phosphorylated eIF2α and the suppression of translation early in reperfusion after transient global brain ischemia.