Irreversible aggregation of protein synthesis machinery after focal brain ischemia

Fangliang Zhang, C. L. Liu, B. R. Hu

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Focal brain ischemia leads to a slow type of neuronal death in the penumbra that starts several hours after ischemia and continues to mature for days. During this maturation period, blood flow, cellular ATP and ionic homeostasis are gradually recovered in the penumbral region. In striking contrast, protein synthesis is irreversibly inhibited. This study used a rat focal brain ischemia model to investigate whether or not irreversible translational inhibition is due to abnormal aggregation of translational complex components, i.e. the ribosomes and their associated nascent polypeptides, protein synthesis initiation factors and co-translational chaperones. Under electron microscopy, most rosette-shaped polyribosomes were relatively evenly distributed in the cytoplasm of sham-operated control neurons, but clumped into large abnormal aggregates in penumbral neurons subjected to 2 h of focal ischemia followed by 4 h of reperfusion. The abnormal ribosomal protein aggregation lasted until the onset of delayed neuronal death at 24-48 h of reperfusion after ischemia. Biochemical study further suggested that translational complex components, including small ribosomal subunit protein 6 (S6), large subunit protein 28 (L28), eukaryotic initiation factors 2α, 4E and 3η, and co-translational chaperone heat-shock cognate protein 70 (HSC70) and co-chaperone Hdj1, were all irreversibly clumped into large abnormal protein aggregates after ischemia. Translational complex components were also highly ubiquitinated. This study clearly demonstrates that focal ischemia leads to irreversible aggregation of protein synthesis machinery that contributes to neuronal death after focal brain ischemia.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalJournal of Neurochemistry
Volume98
Issue number1
DOIs
StatePublished - Jul 1 2006

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Keywords

  • Brain ischemia
  • Chaperone
  • Heat-shock cognate protein 70
  • Protein aggregation
  • Protein synthesis
  • Ribosomal proteins
  • Stress granule
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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