Phosphorylation of the α subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus

Abstract

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and genespecific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2alpha(P) (phosphorylated eIF2alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 191-194]. We show in the present study that one eIF2alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2alpha(P) in these areas. In PKR-deficient animals subjected to SE, eIF2alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2alpha kinase, PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.

Prolonged inflammatory gene response following soman-induced seizures in mice

“…Translation was not assessed in our conditions limiting discussion on the pathophysiological significance of our observations. It is indeed possible that protein expression does not entirely match mRNA synthesis as seizures are reported to depress protein synthesis (Wasterlain, 1974;Carnevalli et al, 2006). As an illustration of such a phenomenon, it was demonstrated that, early in the course of soman intoxication, an increase in hsp70 gene transcription was not followed by translation in the protein HSP72 (Baille Le Crom et al, 1996).…”

Making synaptic plasticity and memory last: mechanisms of translational regulation

“…For example, during ischemia and reperfusion, which often is associated with deficient LTM, there are long-lasting decreases in protein synthesis and increased phosphorylation of eIF2a (DeGracia et al 2002). In addition, increased eIF2a phosphoryation in the brain is associated with epilepsy (Carnevalli et al 2006) and neuronal culture models of Parkinson's disease (PD) (Holtz and O'Malley 2003). Moreover, eIF2a phosphorylation increases in the hippocampus of mouse models of Alzheimer's disease (Page et al 2006;Kim et al 2007), as well as brains of AD patients (Kim et al 2007).…”

Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle

“…In addition, hyperphosphorylation of 4E-BP1, releases eIF4E, thus increasing cap-dependent translation initiation. Stress conditions (e.g., nutrient limitation) have been associated with the phosphorylation of eIF2 (4,48) and the dephosphorylation of 4E-BP1, which would lead to a reduction in protein synthesis (19,24,31). It isunknown, however, whether/how the molecular control of protein synthesis would respond in different tissues when exposed to the same milieu.…”