Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death

Hongmin Wang, Seong Woon Yu, David W. Koh, Jasmine Lew, Carmen Coombs, William Bowers, Howard J. Federoff, Guy G. Poirier, Ted M. Dawson, Valina L. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

The profound neuroprotection observed in poly(ADP-ribose) polymerase-1 (PARP-1) null mice to ischemic and excitotoxic injury positions PARP-1 as a major mediator of neuronal cell death. We report here that apoptosis-inducing factor (AIF) mediates PARP-1-dependent glutamate excitotoxicity in a caspase-independent manner after translocation from the mitochondria to the nucleus. In primary murine cortical cultures, neurotoxic NMDA exposure triggers AIF translocation, mitochondrial membrane depolarization, and phosphatidyl serine exposure on the cell surface, which precedes cytochrome c release and caspase activation. NMDA neurotoxicity is not affected by broad-spectrum caspase inhibitors, but it is prevented by Bcl-2 overexpression and a neutralizing antibody to AIF. These results link PARP-1 activation with AIF translocation in NMDA-triggered excitotoxic neuronal death and provide a paradigm in which AIF can substitute for caspase executioners.

Original languageEnglish (US)
Pages (from-to)10963-10973
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number48
DOIs
StatePublished - Dec 1 2004

Keywords

  • Apoptosis-inducing factor
  • Excitotoxicity
  • NMDA
  • Neuronal death
  • PARP-1
  • nNOS

ASJC Scopus subject areas

  • Neuroscience(all)

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