Parkinson disease (PD), the second most prevalent neurodegenerative disorder, is characterized by loss of dopaminergic (DA) neurons and the formation of protein inclusions that contain the a-synuclein (a-syn) protein. In C. elegans, overexpression of human a-syn, specifically in the eight DA neurons, causes neurodegeneration in an age- and dose-dependent manner, similar to that in PD patients. We are using this C. elegans model of PD to identify the causative factors of this disease. Growing experimental evidence suggest that exposure to environmental toxins may increase the risk of susceptibility to PD. Previously, our lab reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in C. elegans and human neurons (Caldwell et al., 2009, PLoS ONE). We hypothesized that the metabolite could exacerbate neurodegeneration in combination with PD susceptibility gene mutations. Indeed, we report hypersensitivity to the metabolite in C. elegans DA neurons expressing human a-syn in two PD-associated gene mutant backgrounds, pdr-1 (parkin) and djr-1.1 (DJ-1). Using another PD toxin model, 6-hydroxydopamine (6-OHDA), we demonstrate that exposure to more than one environmental risk factor has an additive effect in causing DA neurodegeneration. Evidence from the literature suggests that PD-related toxicants cause mitochondrial dysfunction. Thus, we are examining the impact of the metabolite on mitochondrial function and oxidative stress. Our findings show that DA neurodegeneration induced by the metabolite can be rescued by the mitochondrial complex I activator, Riboflavin and the complex II activator, D-beta-hydroxybutyrate (D-b-HB). Currently, we are further investigating the involvement of mitochondrial complex chains using genetic mutant studies. Using an in vitro assay, we determined that the bacterial metabolite causes excessive production of reactive oxygen species in C. elegans. Also, the anti-oxidant, Probucol, fully rescued metabolite-induced DA neurodegeneration in vivo. Taken together, this study suggests that the S. venezuelae metabolite causes mitochondrial dysfunction and oxidative stress, and ultimately, this leads to neuronal cell death.

Affiliation:
- Biological Sciences, Univ Alabama, Tuscaloosa, AL.