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. Taken together, evidence from both environmental and genetic forms of PD indicates that overloading the ubiquitin-proteasome system (UPS) 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 were originally isolated from bacterial strains within the order Actinomycetales, which are well known for the production of secondary metabolites. There is a high rate of sporadic PD among patients from rural backgrounds where well water and farming potentially represent sources of increased exposure to Actinomycetes. Therefore, to determine if exposure to Actinomycetes could cause DA neurodegeneration, we exposed
dat-1::GFP worms to four species of Streptomyces (S. lividans, S. venezuelae, S. griseus, and S. coelicolor). Interestingly, when L4 larvae of
dat-1::GFP worms were grown on S. lividans and S. venezuelae, they displayed DA neuron degeneration that increased over time, wherein at 4 days exposure 52% and 59% of DA neurons were abnormal, respectively, compared to 19% of worms grown on OP50. DA neuron abnormalities were defined as dendritic changes, cell body rounding, and/or neuron loss. Notably, DA neuron degeneration was not statistically significant following exposure to S. griseus, and S. coelicolor. To determine if the neurodegeneration was specific to DA neurons following exposure to S. lividans and S. venezuelae,
unc-4::GFP and
unc-47::GFP worms were also exposed to these bacterial strains. We did not observe any abnormalities within the cholinergic or GABAergic neurons of these worms. These experiments were performed on NGM; currently we are testing enriched media to determine whether DA neurodegeneration will be enhanced. Additionally, we are analyzing worms exposed to these Streptomyces strains for more generalized stress responses and are attempting to purify the factors responsible for DA neurodegeneration. Future studies will also include examining a combination of environmental and genetic stressors wherein we will assay genetic factors linked to PD in DA neurons following exposure to Streptomycetes and other Actinomycetes.