Apoptosis Inducing Factor in Dopaminergic Cell Death
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DESCRIPTION (provided by applicant) Parkinson's Disease is a chronic progressive neurologic disorder that affects over half a million men and women in the U.S. alone. Underlying the clinical symptoms of Parkinson's Disease is the degeneration of the neuromelanin-containing neurons predominantly located in the pars compacta of the substantia nigra. Although the pathology underlying the disease is clear, it is still unknown why these substantia nigra pars compacta neurons die. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can selectively damage neurons in the nigrostriatal dopaminergic pathway and produce Parkinsonism in humans, non-human primates, and mice has provided a valuable model for investigating mechanisms of selective sensitivity of nigral neurons. MPTP mediates this toxicity through inhibition of complex I in the mitochondria. Excitotoxic and oxidant injury are important mediators in MPTP neurotoxicity. We propose a novel and unique pathway that integrates these classic signals with evolving caspase-independent mitochondrial coordinated pathways of cell death. Apoptosis inducing factor (AIF) is a novel cell death effector protein. It is normally confined to mitochondria but translocates to the nucleus following toxic insults. AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. The morphology of AIF mediated cell death in HeLa cells is reminiscent of excitotoxic morphology in neurons that is induced by NMDA receptor activation, NO release and PARP activation. MPTP is a toxin that induces dopaminergic cell loss and results in experimental animal models of Parkinson's disease. We propose that AIF might be a link between excitotoxicity and known proteins that mediate apoptosis. This proposal is designed to assess the feasibility of this novel avenue of investigation and develop data in support of this innovative hypothesis of neuronal cell death. We propose that excitotoxicity is a unique form of cell death that involves molecules associated with classic necrosis or apoptosis but these mediators are activated in a unique program that ultimately results in excitotoxic death. This hypothesis would be a paradigm shift in the conceptualization of neuronal cell death. Furthermore, understanding the regulation of AIF and its role in excitotoxicity might provide clues to preventing its release from the mitochondria thus providing neurons a window of opportunity to restore NAD levels and survive toxic insults.
