A role for LRRK2 and Neuroinflammatory Processes in Multi-Hit Toxicant Models of Parkinson’s Disease

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SNc) leading to a range of motor behavioral deficits. In addition to motor features, non-motor behaviors are also evident in many cases. Although it has been suggested that genetic mutations represent a cause or risk factor for the disease, there is evidence to suggest that PD arises as a result of the interaction between multiple factors. In the current dissertation, one overarching theme we were interested in was how the behavioral and neurochemical effects of the PD relevant herbicide paraquat might be impacted when combined with different stressors including psychological stress, immune stress, or age induced alterations. We were also highly interested in providing further understanding regarding the role of neuroinflammatory processes (as occurs in PD) in the paraquat induced death of SNc dopamine neurons. In these instances, we focused on the inflammatory regulatory gene (and number one gene implicated in PD), leucine rich repeat kinase 2 (LRRK2). Accordingly, in our study combining paraquat exposure with a chronic unpredictable stress regimen, we found that psychological stressor exposure did not influence the degeneration of midbrain dopamine neurons or accompanying microglia activation induced by the toxin; however, it did influence motor coordination. Conversely, exposure of the pesticide in combination with the inflammatory agent lipopolysaccharide (LPS) augmented SNc cell loss. In these studies using LPS, we found that knocking out LRRK2 protected against the loss of midbrain dopamine neurons and behavioral deficits, induced by LPS priming followed by paraquat exposure. In fact, knocking out LRRK2 altered the pro-inflammatory microglia phenotype that is typically induced by LPS exposure. Likewise, LRRK2 deficiency protected against the paraquat induced peripheral and central toxic effects in mice older than what we typically use. Taken together, our results support the hypothesis that the interaction between different stressors can impact behavioral and biological outcomes relevant for PD, and LRRK2 is important for the toxic effects of paraquat, and LPS priming with later paraquat exposure. The data presented herein may also provide important implications for the development of treatment strategies that target inflammatory processes in PD.