Neurodegenerative diseases such as Parkinson disease (PD) comprise a major societal burden with increasing occurrence as our mean population ages. Recent studies have demonstrated that bacteria of distinct Streptomyces species have the capacity to produce a neurotoxic metabolite that causes dopaminergic degeneration in the nematode model organism C. elegans and in human SH-SY5Y neuroblastoma cells. These bacteria are commonly found in soil environments and exposure to their excretions may be a contributor to PD, which is more prevalent in individuals with a rural lifestyle. While exposures to pesticides may be a partially responsible, these alone cannot account for prevalence of PD, even in rural areas. This R15 proposal utilizes C. elegans as a primary assay system for scoring dopamine (DA) neuron degeneration to explore mechanisms involved in Streptomyces-induced neurodegeneration. While chronic exposures to the toxic metabolite cause DA neurodegeneration, experiments will be performed to determine if acute exposure paradigms also result in neurodegeneration (Aim I). Established mutant and transgenic worm strains will be utilized to investigate whether differential degeneration is observed in distinct genetic backgrounds related to PD (Aim II). Cellular pathways associated with neurodegeneration, such as apoptosis, DA metabolism and mitochondrial function will also be assessed following exposure to the metabolite (Aim III). Finally, studies in human neuronal cell cultures will be conducted, both to validate results gleaned from the invertebrate system and to expand upon data demonstrating that the neurotoxic activity of the Streptomyces metabolite extends to these cultures (Aim IV). Taken together, these studies represent an integrated strategy to rapidly discern the significance of this novel environmental factor and its influence on neurodegeneration as it pertains to PD. Included among the broader impacts of this proposal are an understanding of one possible cause of health disparities in rural populations, in addition to training and mentorship of graduate and undergraduate students.
Parkinson's Disease (PD) is the most common movement disorder affecting over 1 million Americans, yet underlying causes of this neurodegenerative disease have largely eluded medical science. This proposal is designed to address an unmet challenge of discerning environmental factors that contribute to PD by investigating the potential for exposures to a toxic compound produced by common soil bacteria to enhance susceptibility to neurodegeneration over the course of aging. Through an integrated training and experimental strategy involving student-centered research, mechanisms underlying neurotoxicity will be explored using a whole animal model system, as well as human cell culture experiments, whereby outcomes include potentially establishing a new paradigm for understanding neurodegeneration that may aid in the development of models to advance diagnostic and therapeutic strategies to combat PD.
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| Martinez, B A; Kim, H; Ray, A et al. (2015) A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans. Cell Death Dis 6:e1908 |
| Ray, A; Martinez, B A; Berkowitz, L A et al. (2014) Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model. Cell Death Dis 5:e984 |
