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.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Active Transport, Cell Nucleus
- Animals
- Apoptosis / drug effects*
- Apoptosis / physiology
- Apoptosis Inducing Factor
- Caspases / physiology
- Cells, Cultured / cytology
- Cells, Cultured / drug effects
- Cells, Cultured / physiology
- Cerebral Cortex / cytology
- Cerebral Cortex / embryology
- Corpus Striatum / drug effects
- Corpus Striatum / metabolism
- Cysteine Proteinase Inhibitors / pharmacology
- Cytochromes c / analysis
- DNA Damage
- Enzyme Activation / drug effects
- Excitatory Amino Acid Agonists / toxicity*
- Flavoproteins / physiology*
- Genes, bcl-2
- Glutamic Acid / physiology
- Injections
- Intracellular Membranes / physiology
- Membrane Potentials / drug effects
- Membrane Proteins / physiology*
- Mice
- Mice, Knockout
- Mitochondria / metabolism
- N-Methylaspartate / toxicity*
- Neurons / drug effects*
- Neurons / physiology
- Nitric Oxide / physiology
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases / deficiency
- Poly(ADP-ribose) Polymerases / genetics
- Poly(ADP-ribose) Polymerases / physiology
- Proto-Oncogene Proteins c-bcl-2 / biosynthesis
- Proto-Oncogene Proteins c-bcl-2 / physiology
- Signal Transduction / drug effects
- Signal Transduction / physiology
- Transfection
- alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity
Substances
- Apoptosis Inducing Factor
- Cysteine Proteinase Inhibitors
- Excitatory Amino Acid Agonists
- Flavoproteins
- Membrane Proteins
- AIFM1 protein, mouse
- Proto-Oncogene Proteins c-bcl-2
- Nitric Oxide
- Glutamic Acid
- N-Methylaspartate
- alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
- Cytochromes c
- Parp1 protein, mouse
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
- Caspases