Phosphorylation of the α subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat

Bürda, Jozef; Martı́n, M. Elena; Garcı́a, Ana Maria; Alcázar, Alberto; Fando, Juan L.; Salinas, Matilde

doi:10.1042/bj3020335

Cited by 101 publications

(112 citation statements)

References 37 publications

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“…A key feature of transient cerebral ischemia is the blocking of translation at the initiation step, as indicated by severe suppression of the incorporation of amino acids into proteins, increased phosphorylation of the eukaryotic initiation factor 2␣ (eIF2␣), and disaggregation of polyribosomes (1)(2)(3). To date, the only eIF2␣ kinase shown to be activated after transient ischemia is the double-stranded RNA-dependent protein kinase-like endoplasmic reticulum (ER) kinase (4), an enzyme specifically activated under conditions associated with ER stress (5).…”

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confidence: 99%

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no upregulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.

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confidence: 99%

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Accordingly, PKR expression in mouse brain has been found particularly high in the neocortex and hippocampus (http://www.brain-map.org/), where SV replication was easily detected. Interestingly, phosphorylation of eIF2 in cortical neurons has been reported to occur during ischemic stress and other pathological situations, such as Alzheimer's and Huntington diseases (43)(44)(45)(46)(47). By means of recombinant viruses expressing engineered reporter mRNAs, we present indirect but solid evidence that translation of nonviral mRNA is strongly inhibited in infected mouse-brain neurons.…”

Section: Discussionmentioning

confidence: 75%

Inhibition of host translation by virus infection in vivo

Toribio

Ventoso

2010

Proc. Natl. Acad. Sci. U.S.A.

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Infection of cultured cells with lytic animal viruses often results in the selective inhibition of host protein synthesis, whereas viral mRNA is efficiently translated under these circumstances. This phenomenon, known as "shut off," has been well described at the molecular level for some viruses, but there is not yet any direct or indirect evidence supporting the idea that it also should operate in animals infected with viruses. To address this issue, we constructed recombinant Sindbis virus (SV)-expressing reporter mRNA, the translation of which is sensitive or resistant to virus-induced shut off. As found in cultured cells, replication of SV in mouse brain was associated with a strong phosphorylation of eukaryotic initiation factor (eIF2) that prevented translation of reporter mRNA (luciferase and EGFP). Translation of these reporters was restored in vitro, in vivo, and ex vivo when a viral RNA structure, termed downstream hairpin loop, present in viral 26S mRNA, was placed at the 5′ end of reporter mRNAs. By comparing the expression of shut off-sensitive and -resistant reporters, we unequivocally concluded that replication of SV in animal tissues is associated with a profound inhibition of nonviral mRNA translation. A strategy as simple as that followed here might be applicable to other viruses to evaluate their interference on host translation in infected animals.eukaryotic initiation factor-2 phosphorylation | dsRNA-dependent protein kinase | Sindbis

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“…The main reason for postischemic translation inhibition is the α subunit phosphorylation of initiation factor eIF-2 (Burda et al 1994). Phosphorylation is caused by a transient decrease in activity of protein phosphatases PP-1 and PP-2B (Martin de la Vega et al 2001) as well as activation of initiation factor 2α kinase (PERK) (Kumar et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro translation was assessed in a cell-free system as previously reported (Burda et al 1994). The complete reaction system in a final volume of 50 μl contained: 50 mmol/l Hepes-KOH, pH 7.55; 140 mmol/l potassium acetate; 4 mmol/l magnesium acetate; 2.5 mmol/l dithiothreitol; 0.32 mol/l sucrose; 1 mmol/l ATP; 0.75 mmol/l GTP; 20 mmol/l phosphocreatine; 150 μg/ml creatine phosphokinase; 50 μmol/l amino acids, 100 μg of PMS proteins and 0.3 μCi of [ 14 C]-leucine (8.88 GBq/mmol).…”

Section: In Vitro Translationmentioning

confidence: 99%

“…After brainwide transient inhibition of initiation, most brain regions recover their protein synthesis capability; however, in the selectively vulnerable regions, the inhibition of protein synthesis is persistent (Thilmann et al 1986;Widmann et al 1991;Kato et al 1995). Deep inhibition of translation occurring immediately after restoration of blood flow to ischemic brain tissue seems to be caused mainly by phosphorylation of the α subunit (38 kDa) of eukaryotic initiation factor 2 (eIF-2) (Burda et al 1994;DeGracia et al 1996). The impact of this translational inhibition lies in the fact that this inhibition is practically irreversible in the selectively vulnerable neuronal populations of the brain (Thilmann et al 1986;Widmann et al 1991).…”

Section: Introductionmentioning

confidence: 99%

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Effect of L-carnitine on postischemic inhibition of protein synthesis in the rat brain

Bürda¹,

M²,

Danielisová³

et al. 2009

gpb

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Abstract. The purpose of this study was to investigate effects of carnitine administration on protein synthesis recovery after transient cerebral ischemia. Rats received L-carnitine in two doses of 16 mmol/kg i.p. 15 min before ischemia and just on the onset of reperfusion. Transient forebrain ischemia was induced by 4-vessel occlusion for 15 min, followed by 30 min or 7 days of reperfusion. Protein synthesis rate, reinitiation ability and neurodegeneration in the frontal cortex and hippocampus were measured by the incorporation of radioactively labelled leucine into polypeptide chains in postmitochondrial supernatants and by Fluoro-Jade B staining.A protective effect was observed, on protein synthesis as well as the number of surviving neurons, in the L-carnitine-treated groups. Our results indicate that L-carnitine can exert a protective effect in the development of reperfusion-induced injury. L-carnitine significantly reduced the ischemia/reperfusion-induced inhibition of translation and neurodegeneration in the neocortex as well as in the highly sensitive hippocampus and dorsolateral striatum. We expect that the ability of L-carnitine to keep translational machinery on facilitates efficacy of postischemic remodulation of gene expression.

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Phosphorylation of the α subunit of initiation factor 2 correlates with the inhibition of translation following transient cerebral ischaemia in the rat

Cited by 101 publications

References 37 publications

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Inhibition of host translation by virus infection in vivo

Effect of L-carnitine on postischemic inhibition of protein synthesis in the rat brain

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