This proposal is designed to pursue our exploration of the pathogenesis of Parkinson's disease (PD). Pertinent to this goal, it has been found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) as seen in PD, can kill these neurons by apoptosis. We have demonstrated that MPTP-induced SNpc DA neuron apoptosis is Bax-dependent and involves the recruitment of the mitochondrial apoptotic pathway. This molecular cascade cannot be recapitulated by MPTP in isolated brain mitochondria, supporting the notion that MPTP triggers the apoptotic demise of SNpc DA neurons by an indirect mitochondrial mechanism in which Bax is pivotal. Accordingly, Specific Aim (SA)-I will determine how Bax is upregulated after MPTP by studying the role of the tumor suppressor p53, one of the rare identified molecules known to regulate Bax expression. Since activation of p53 results, in turn, from DNA damage, we will assess the relationship between DNA damage, p53 activation and Bax upregulation after MPTP intoxication, as well as the dependence of this molecular cascade on MPTP-induced oxidative stress. In SA-II, we will determine how Bax is activated after MPTP by assessing the contribution of the JNK/c-Jun pathway on Bax oligomerization and mitochondrial insertion, which constitute the cornerstone of Bax pro-apoptotic effect. The specific JNK isoform responsible for this effect will be determined, as well as the role of the """"""""BH3-only"""""""" molecule Bim. In SA-IIi, we will assess the occurrence of the caspase-independent apoptotic pathway mediated by apoptosis inducing factor (AIF), and its regulation by Bax, in the MPTP mouse model. Accordingly, we will determine the time-course of AIF mitochondrial release and nuclear translocation after MPTP intoxication in mice with and without ablation/inhibition of caspases, and its dependency on Bax and PARP activations. We will also test, in isolated brain mitochondria, whether AIF release directly results from the inhibitory effect of MPTP on mitochondrial respiration. Finally, the actual role of AIF in MPTP-induced SNpc DA neurodegeneration will be demonstrated in mutant mice with 80% reduction in AIF expression with and without caspase inhibition. Collectively, the proposed studies should shed light on the molecular mechanisms of neurodegeneration in PD and help to identify new molecular targets for therapeutic intervention.
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