Mechanisms of pesticide-induced neuroinflammation and parkinsonism in aging mice.

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PROJECT SUMMARY Complex gene-environment interactions underlie the incidence and progression of Parkinson’s disease (PD). Our work in pesticide-exposed mice and PD patients indicates that cellular stress associated with environmental toxicant exposure activates the intracellular inflammasomes. Inflammasomes are intracellular multi-protein complexes containing pattern recognition receptors that initiate and propagate inflammation. Inflammasomes have emerged as key mediators of inflammation in neurodegenerative diseases in part because they can sense non-microbial “sterile” inflammatory triggers commonly observed in chronic, age-related disorders like PD. Inflammasome triggers identified in models of PD include pesticides, heavy metals, mitochondrial and oxidative stress, and proteinaceous insults like misfolded synuclein. Our original aims determined that long-term exposure to the PD-associated pesticide rotenone activated the NLRP3-inflammasome and that Nlrp3-/- mice were protected from rotenone-induced nigral cell loss. In parallel studies, we identified elevated NLRP3 expression in degenerating mesencephalic tissues and plasma in PD patients compared with healthy volunteers. These findings and rapidly advancing efforts to target NLRP3 in the clinic provide a compelling backdrop for continued analysis of the activities of the NLRP3-inflammasome in the central nervous system. We propose to extend our studies based on our findings of both microglial and neuronal origins for NLRP3-inflammasome activity and the concept that plasma borne inflammasome-related proteins may be a novel class of biomarkers for toxicant exposure and PD. We’ve developed innovative mouse models based on CRE-driven dopamine neuron and microglial specific Nlrp3 gain-of function. We will utilize our established rotenone exposure model to dissect the contributions of cell-type specific NLRP3 inflammasome activity to neuroinflammation and nigral neurodegeneration. In a second aim, we will work to understand the cellular mechanisms that underlie our detection of plasma-borne inflammasome related proteins in PD patient plasma. These studies will validate LC- MS/MS studies in which we identified Nlrp3-dependent release of the exocytosis mediators Bruton’s Kinase (BTK) and Coronin1A (CORO1A). We propose systematic NLRP3, BTK, and CORO1A gain-and-loss of function studies in genetically modified pesticide-exposed microglial, neuronal, and monocytic cell lines to characterize novel secretory mechanisms and define brain-cell-type specific NLRP3-dependent secretomes. Studies will provide mechanistic data and define molecules secreted specifically by distressed brain cells providing a foundation for the development of diagnostic tools to detect, stratify, and monitor PD. Our study is important because we work to combat the rapidly increasing global burden of age-related neurodegenerative disorders by characterizing a pathway common to multiple diseases that can be targeted with already existing or emerging small molecule therapeutics.