Title

Cerebral ischemia and the unfolded protein response

Document Type

Article

Publication Date

2004

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.

Publication Title

Journal of neurochemistry

Volume

91

Issue

1

First Page

1

Last Page

8

Comments

This article was published in Journal of neurochemistry, Volume 91, Issue 1, Pages 1-8.

The published version is available at http://dx.doi.org/10.1111/j.1471-4159.2004.02703.x.

Copyright © 2004 ISN.

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