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The Journal of Neuroscience, December 1, 2004, 24(48):10963-10973; doi:10.1523/JNEUROSCI.3461-04.2004

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Neurobiology of Disease
Apoptosis-Inducing Factor Substitutes for Caspase Executioners in NMDA-Triggered Excitotoxic Neuronal Death

Hongmin Wang,^1,2 * Seong-Woon Yu,^1,2 * David W. Koh,^1,2 Jasmine Lew,^1,2 Carmen Coombs,^1,2 William Bowers,⁵ Howard J. Federoff,⁵ Guy G. Poirier,⁶ Ted M. Dawson,^1,2,3 and Valina L. Dawson^1,2,3,4

¹Institute for Cell Engineering and Departments of ²Neurology, ³Neuroscience, and ⁴Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ⁵Department of Neurology, Center for Aging and Developmental Biology, University of Rochester, Rochester, New York 14642, and ⁶Health and Environment Unit, Laval University Medical Research Center, Centre Hospitalier Universitaire de Québec, Ste-Foy, Quebec G1V 4G2, Canada

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.

Key words: apoptosis-inducing factor; NMDA; neuronal death; PARP-1; excitotoxicity; nNOS

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Received May 8, 2004; revised October 19, 2004; accepted October 24, 2004.

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