期刊
JOURNAL OF NEUROSCIENCE
卷 24, 期 48, 页码 10963-10973出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3461-04.2004
关键词
apoptosis-inducing factor; NMDA; neuronal death; PARP-1; excitotoxicity; nNOS
资金
- NINDS NIH HHS [P01 NS039148, NS39148] Funding Source: Medline
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.
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