This proposal is designed to pursue our studies 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 kills dopaminergic (DA) neurons of the substan tia nigra pars compacta as seen in PD, can execute these neurons by the molecularly regulated form of cell death termed programmed cell death (PCD).

However, at present there are no molecular tools of potential therapeutic significance to interfere with this process. In keeping with this, we have previously demonstrated that activation of Bax, a potent pro-cell death protein, governs the PCD of DA neurons in this PD model, and it has been shown that Bax is also activated in PD human brain tissues. However, it is not known what controls the conversion of Bax from the inactive to the active conformation. Recent evidence indicates that activation of Bax requires interaction with the small BH3-only proteins of the Bcl-2 family.

Accordingly, Specific Aim I (SA-I) will define the role of BH3-only molecules Puma and Noxa in MPTP-related Bax activation and DA neurodegeneration and its dependency on the transcription factor p53. SA-II will determine the occurrence of a transcription-independent role for p53 at the level of the mitochondria on MPTP-related Bax activation and DA neurodegeneration. SA-III will determine the role of BH3-only molecule Bim in MPTP-induced Bax activation and DA neurodegeneration and its dependency on the c-Jun N-terminal kinase (JNK) pathway.

Finally, SA-IV will assess the effect of two new molecules that interfere with Bax activation as potential therapeutic tools for PD-related DA neurodegeneration. Overall, this proposal should (i) lay the ground for the development of novel therapeutic strategies for PD and (ii) allow my professional integration to European research by providing substantial funding to develop my own research group in Spain.