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Cerebral ischemia and the unfolded protein response
Author(s) -
DeGracia Donald J.,
Montie Heather L.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02703.x
Subject(s) - unfolded protein response , atf6 , endoplasmic reticulum , downregulation and upregulation , microbiology and biotechnology , apoptosis , transcription factor , programmed cell death , biology , chemistry , gene , biochemistry
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 eIF2α, 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 eIF2α(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.