Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

Parkinson's disease (PD) results from the progressive loss of dopamine producing neurons in the Substantia Nigra pars comapcta (SNc). This loss is thought to occur over several years to decades and current evidence suggests that neuroinflammation may play a central role in this loss. Numerous epidemiological studies have implicated chronic exposure to environmental toxicants such as heavy metals and pesticides to risk of developing PD. Indeed, many of these risk factors have been validated as rodent models of PD, able to induce dopaminergic cell loss in the SNc as well as motor dysfunction. While research strongly supports a role for environmental toxicants and inflammation in PD relatively little work has examined the interactions between these toxicants and other risk factors including senescence, genetic vulnerabilities, the gut microbiota or immunogens. Thus, the present dissertation set out to investigate the interactions between these factors in PD to determine which factors may be of greatest relevance in further animal models of the disease.We presently demonstrated that interaction of diverse environmental and genetic factors contributed to the neuroinflammatory and PD-like neurodegeneration. We found that exposure to paraquat led to neuroinflammatory consequences persisting over six months and provide evidence that at this time point further inflammatory processes arise. We also found that LPS and paraquat treatment did not significantly alter the gut microbiome or gut inflammasome; however, in combination with dextran sodium sulphate (DSS) we found greatly increased pro-inflammatory factors. Using mice overexpressing the LRRK2 gene, G2019S, we found no changes in sickness, inflammation or neurodegeneration following paraquat treatment. However, the G2019S over-expressing mice did display augmented stressor effects. Further experiments revealed that G2019S knockin mice showed increased signs of inflammation and this was that was reversed by the CSF-1 antagonistic drug, PLX-3397. Ultimately these data support the role of environmental factors in PD including alterations to the gut microbiome, however, these findings suggest that such factors may not be an immediate PD cause but rather may exert their influence over a longer period of time.