Parkinsons disease (PD) involves the progressive loss of dopamine (DA) neurons from the substantia nigra pars compacta (SNpc). Genetic forms of PD account for only 5-10% of known cases and environmental factors appear pivotal to sporadic causality. Evidence from both environmental and genetic studies of PD indicates that overloading the ubiquitin-proteasome system is a causative risk factor for PD. Furthermore, when proteasome inhibitors were injected directly into the brains of rats, PD-like symptoms resulted (McNaught et al., 2004; Ann Neurol. 56:149-162). Many proteasome inhibitors are isolated from bacterial strains within the order Actinomycetales, which are well known for the production of secondary metabolites. To determine if exposure to Actinomycetes could cause DA neurodegeneration in C. elegans, we exposed worms to three different species of Streptomyces (S. venezuelae, S. griseus, and S. coelicolor). When worms were grown on either S. griseus or S. coelicolor no DA neurodegeneration was observed. However worms exposed to S. venezuelae displayed DA neurodegeneration that increased over time. The causual factor is excreted by S. venezuelae, as conditioned media is sufficient for the neurodegenerative effect. This factor does not enter DA neurons through the DA transporter because degeneration is observed in
dat-1 mutant animals. Further characterization of the S. venezuelae activity shows that DA degeneration does not result from generalized stress response or the unfolded protein response but may occur as a result of proteasome inhibition. Initial efforts to purify the factor have revealed that it is lipophilic and does not fit the molecular profile of known proteasome inhibitors.