Subcellular stress response and induction of molecular chaperones and folding proteins after transient global ischemia in rats

Jessie S. Truettner, Kurt Hu, Cindy L. Liu, W. Dalton Dietrich, Bingren Hu

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Brain ischemia induces the toxic accumulation of unfolded proteins in vulnerable neurons. This cellular event can trigger the unfolded protein response (UPR) and activate the expression of a number of genes involved in pro-survival pathways. One of the pro-survival pathways involves the sequestration and elimination of misfolded and aggregated proteins. Recent evidence suggests that the endoplasmic reticulum (ER), mitochondria, and cytoplasm respond individually to the accumulation of unfolded proteins by induction of organelle specific molecular chaperones and folding enzymes. This study utilized a rat model of transient (15 min) global ischemia (2-vessel occlusion) to investigate the regional and temporal induction of some of these key stress proteins after ischemia. Electron microscopy demonstrated that visible protein aggregates accumulated predominately in the cytoplasm. We used in situ hybridization (forebrain structures) and western blot (hippocampus) analysis to measure changes in expression of heat shock protein 70 (HSP70 cytoplasmic), HSP60 (mitochondrial), ER luminal proteins glucose response proteins GRP78 and GRP94, protein disulphide isomerase (PDI), homocysteine-inducible, endoplasmic reticulum stress-inducible protein (HERP), and calnexin. Induction of mRNA for HSP70 occurred earlier (beginning at 30 min) and at a higher level relative to the delayed (4-24 h) and more moderate induction of mRNAs for mitochondrial matrix HSP60 and the ER lumen HERP, GRP78, GRP94, calnexin and PDI. Increases in hippocampal proteins were observed at 4 h (HSP70) and 24 h (HSP60, GRP78, GRP94) after reperfusion. These results demonstrate that after a transient ischemic insult, the subcellular responses to the accumulation of unfolded proteins varies between cellular compartments and are most prevalent in the cytoplasm and, to a lesser degree, in the mitochondrial matrix and ER lumen.

Original languageEnglish (US)
Pages (from-to)9-18
Number of pages10
JournalBrain research
Volume1249
DOIs
StatePublished - Jan 16 2009

Keywords

  • Brain ischemia
  • CA1 hippocampus
  • Chaperone and folding protein
  • Herp-GRP78-GRP94-calnexin-PDI-HSP70-HSP60
  • Protein aggregation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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