Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage

Mol Brain. 2014 Mar 27:7:20. doi: 10.1186/1756-6606-7-20.

Abstract

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is conventionally considered a critical enzyme that involves in glycolysis for energy production. Recent previous studies have suggested that GAPDH is important in glutamate-induced neuronal excitotoxicity, while accumulated evidence also demonstrated that GAPDH nuclear translocation plays a critical role in cell death. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we showed that GAPDH translocates to the nucleus in a Siah1-dependent manner upon glutamate stimulation. The nuclear GAPDH forms a protein complex with p53 and enhances p53 expression and phosphorylation. Disruption of the GAPDH-p53 interaction with an interfering peptide blocks glutamate-induced cell death and GAPDH-mediated up-regulation of p53 expression and phosphorylation. Furthermore, administration of the interfering peptide in vivo protects against ischemia-induced cell death in rats subjected to tMCAo. Our data suggest that the nuclear p53-GAPDH complex is important in regulating glutamate-mediated neuronal death and could serve as a potential therapeutic target for ischemic stroke treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / enzymology
  • Brain Ischemia / pathology*
  • Cell Death / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cytoprotection* / drug effects
  • Disease Models, Animal
  • Glutamic Acid / pharmacology
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
  • HEK293 Cells
  • Humans
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Kainic Acid / pharmacology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology*
  • Neuroprotective Agents / pharmacology
  • Nuclear Proteins / metabolism
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Neuroprotective Agents
  • Nuclear Proteins
  • Receptors, AMPA
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • Glutamic Acid
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • glutamate receptor ionotropic, AMPA 2
  • Kainic Acid
  • glutamate receptor ionotropic, AMPA 1