One of the main features of Parkinson's disease (PD) is the loss of dopaminergic (DA) neurons. Only 5-10% of PD has been associated with a genetic cause, and it is thought that the environment, or a combination of environment and genetic factors, might lead to the loss of DA neurons. We have identified a species of soil bacteria, Streptomyces venezuelae, which produce a metabolite that causes neurodegeneration of C.elegans DA neurons and cultured human DA neurons (Caldwell et al., 2009, PLoS ONE). We hypothesize that exposure to this metabolite might be associated with PD, in association with a genetic predisposition to neurodegeneration. In this regard, we have previously identified gene products associated with DA neurodegeneration that are involved in ER to Golgi, or autophagy-lysosomal trafficking (Gitler et al., 2008, PNAS, Hamamichi et al., 2008, PNAS, and Gitler et al., 2009, Nature Genet). These gene products include SEC-22, PARK9, VPS41, ATG7, Rab 1, Rab3A, Rab8A, and ULK2/UNC-51. In this study, the DA neurons of C.elegans with mutations in theses genes were examined for their response to exposures with the bacterial metabolite. Animal containing a mutation in a gene involved in ER to Golgi trafficking,
sec-22(
ok3053), displayed exacerbated DA neurodegeneration in combination with the metabolite. Mutations in genes associated with autophagy-lysosomal trafficking also displayed enhanced DA neurodegeneration in the presence of the metabolite; however, the response observed in these mutants [
unc-51(
e369) and
catp-6(
ok3473)] was less pronounced and delayed. Current studies on the remaining gene products, where mutants are unavailable, are being investigated using DA neuron-specific RNAi for differential neuroprotective activity against the metabolite. Candidates that, when depleted, display a toxicity phenotype, will also be overexpressed in DA neurons and assayed for neuroprotective activity against the metabolite. Taken together, pathway-specific candidates that have a toxin-modulating effect will assist in assigning a functional role for the metabolite within neurons.