Cerebral ischemia and the unfolded protein response

Abstract

We review studies of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) following cerebral ischemia and reperfusion (I/R). The UPR is a cell stress program activated when misfolded proteins accumulate in the ER lumen. UPR activation causes: (i) a PERK-mediated phosphorylation of eIF2a, inhibiting protein synthesis to prevent further accumulation of unfolded proteins in the ER and (ii) upregulation of genes coding for ER-resident enzymes and chaperones and others, via eIF2a(p), and ATF6 and IRE1 activation. UPR-induced transcription increases capacity of the ER to process misfolded proteins. If ER stress and the UPR are prolonged, apoptosis ensues. Multiple forms of ER stress have been observed following brain I/R. The UPR following brain I/R is not isomorphic between in vivo I/R models and in vitro cell culture systems with pharmacological UPR induction. Although PERK and IRE1 are activated in the initial hours of reperfusion, total PERK decreases, ATF6 is not activated, and there is delayed appearance of UPR-induced mRNAs. Thus, multiple damage mechanisms associated with brain I/R alter UPR expression and contribute to a pro-apoptotic phenotype in neurons. Insights resulting from these studies will be important for the development of therapies to halt neuronal death following brain I/R. It has been known for three decades that protein synthesis inhibition (PSI) occurs in brain neurons during reperfusion following global and focal ischemia (Hossmann 1993). The first identified molecular mechanisms of PSI were traced to signaling modifications in the eukaryotic initiation factors (eIF) that control global rates of protein synthesis: eIF2 and eIF4 (DeGracia et al. 2002). This raised the question as to how cerebral ischemia and reperfusion (I/R) lead to signaling modifications in the translational machinery of the neuron. An independent line of investigation revealed that depletion of endoplasmic reticulum (ER) Ca 2+ stores, a form of ER stress, caused PSI (Brostrom and Brostrom 1998). This observation was brought to bear on PSI following brain I/R, with the suggestion that ER stress is one of the cellular pathologies induced by ischemia (Paschen 1996). Subsequently, a set of interlinked molecular pathways activated in response to ER stress have been described, and collectively these pathways are referred to as the unfolded protein response (UPR; Kaufman 1999). The purpose of the present review is to critically evaluate studies showing that ER stress and UPR activation occur following brain I/R. A major result of these studies is that expression of the UPR is not isomorphic between in vivo I/R models and in vitro cell culture systems where the UPR is pharmacologically induced. Although PERK and IRE1 are activated during initial reperfusion, total PERK levels decrease, ATF6 is not activated, and there is a delay in appearance of UPR-induced mRNAs following brain I/R. These observations indicate that

Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat

“…A defect in mRNA regulation is also consistent with lack of translation of HSP70 protein in CA1 in spite of its copious transcription, 33,[54][55][56][57][58][59] which was also observed for stress mRNAs induced by the unfolded protein response. [60][61][62] Differences in mRNA handling by CA1 and CA3 are supported by our observation that HuB, HuC, and HuD are absent in CA1, but not CA3, control neurons.…”

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

“…For example, ischemia reperfusion, which results in inflammatory injury, is associated with induction of UPR target genes and XBP-1 splicing [48,49]. In the liver, damage has been shown to occur through a TLR4-mediated IRF3-dependent mechanism implicating endogenous TLR4 ligands, and raising the possibility that synergistic IFN-b induction might contribute to ischemia reperfusion injury [50].…”

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

“…ER stress has recently been believed to be involved in the pathogenesis of neurodegenerative diseases including AD (DeGracia and Montie, 2004;Katayama et al, 2004;Lindholm et al, 2006;Smith et al, 2005). e-IF2a is known to be phosphorylated by some kinases including PKR, PERK, HRI, and GCN2 under various stresses such as ER stress (Taylor et al, 2005).…”

“…Prolonged ER stress is linked to the pathogenesis of several neurodegenerative disorders, which include cerebral ischemia, PD, and AD (DeGracia and Montie, 2004;Katayama et al, 2004;Smith et al, 2005).…”