Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12

N Badiola, C Penas, A Miñano-Molina, B Barneda-Zahonero, R Fadó, G Sánchez-Opazo, JX Comella, J Sabriá, C Zhu, K Blomgren, C Casas, J Rodríguez-Alvarez

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120 Citations (Scopus)

Abstract

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2αdirected phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress. © 2011 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Article numbere149
Pages (from-to)1-8
JournalCell Death and Disease
Volume2
Issue number4
DOIs
Publication statusPublished - 1 Jan 2011

Keywords

  • Apoptosis
  • Brain
  • Caspase-12
  • Cell culture
  • Endoplasmic reticulum stress
  • Ischemia

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