Interaction of Pyrethroid Exposure and the Microbiome on Parkinson's Disease related Pathologies

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Project Summary Pesticide exposures are a significant risk factor for many neurodegenerative diseases, including Parkinson’s disease (PD). Sporadic PD, with no known etiology accounts for ~90% of disease incidences, as highly penetrant genetic risks are not very prevalent. Experimental models have largely elucidated molecular mechanisms of pesticide exposures directly on those neurons vulnerable during PD. For instance, exposures to rotenone and MPTP are used to induce nigrostriatal neuron loss in rodents. While the effects of these exposures on the central nervous system (CNS) have been explored, outcomes of PD-relevant exposures in peripheral organs, such as the intestine, are largely unknown. Gastrointestinal (GI) dysfunctions, such as constipation and inflammatory bowel disease often precede PD diagnosis, and loss of GI innervation appears prior to CNS pathology in some PD-predisposed populations. It is likely that GI pathologies may signal the onset of CNS dysfunctions in PD. Within the GI tract, alterations to the microbiome (i.e. dysbiosis) are established to arise during PD, and specific alterations to bacterial taxa correlate with disease severity. Dysbiosis is not simply an epiphenomenon, but has physiological impacts on the host, particularly in the context of PD. Intestinal inflammation and dysbiosis are sufficient to exacerbate CNS pathology and motor dysfunctions in animal models of PD. Intriguingly, the PD- derived microbiome is enriched for bacterial genes involved in xenobiotic metabolism, indicating that pesticide exposures shape the GI environment. We therefore predict that dysbiosis, resultant from pesticide exposure, impacts PD-relevant GI and CNS pathologies. Here, we will use germ-free (GF) mice as tool to determine microbiome contributions to pesticide-induced pathologies. Most importantly, we will identify the contributions of dysbiosis to established nigrostriatal dysfunctions that arise following pesticide exposure. Combining microbial effects with relevant toxicant exposure, we will test the interaction of these external influences in a transgenic mouse model of PD. This proposed project will bridge a gap in our understanding of how exposure to environmental toxicants influences neurodegenerative outcomes. We hypothesize intestinal pyrethroid exposure impacts microbiome architecture, which modulates inflammatory responses, and exacerbates PD-relevant outcomes in the GI and nigrostriatal system. This project will provide a foundation for uncovering microbe- environment interactions that modulate risk of neurodegenerative disease.