Chemical Genomic Profiling for Identifying Intracellular Targets of Toxicants Producing Parkinson’s Disease

The yeast deletion collection includes ~4700 strains deleted for both copies of every nonessential gene. This collection is a power-ful resource for identifying the cellular pathways that functionally interact with drugs. In the present study, the complete pool of ~4700 barcoded homozygous deletion strains of Saccharomyces cerevisiae were surveyed to identify genes/pathways interacting with 1-methyl-4-phenylpyridinium (MPP+) and N,N-dimethyl-4-4-bipiridinium (paraquat), neurotoxicants that can produce Parkinson’s disease. Each yeast mutant is molecularly ‘‘barcoded’’ the collections can be grown competitively and ranked for sen-sitivity by microarray hybridization. Analysis data from these screens allowed us to determine that the multivesicular body pathway is an important element of toxicity induced by both MPP+ and paraquat. When yeast genes that when deleted showed sensitivity to MPP+ and paraquat toxicity were analyzed for their homology to human genes, 80 % were found to have highly conserved human homologs (with e < 108). Future work will address if these human genes may also functionally interact with MPP+ and paraquat toxicity. Key Words: chemogenomics; neurotoxicants; Parkinson’s disease. The search for a link between environmental factors and the risk of developing Parkinson’s disease (PD) has been investi-gated for over 20 years. One interesting observation is that the structurally simple molecule, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) could induce many of the motor features of PD in humans (Langston, 1985; Langston et al., 1984). In the intervening years, many studies have highlighted links between PD and exposure to insecticides and herbicides (Hertzmann et al., 1990; Seidler et al., 1996). However, to date no causative agent has been unequivocally identified. One of the few compounds linked to PD is paraquat (N,N-dimethyl-4-4