Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene result in late-onset Parkinson's disease. The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of Parkinson's disease suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. Since neuroinflammation is commonly associated with the pathogenesis of Parkinson's disease, we examine a potential role of mutant LRRK2 in regulation of the immune response and inflammatory signalling in vivo. Here, we show that mice overexpressing human pathogenic LRRK2 mutations, but not wild-type mice or mice overexpressing human wild-type LRRK2 exhibit long-term lipopolysaccharide-induced nigral neuronal loss. This neurodegeneration is accompanied by an exacerbated neuroinflammation in the brain. The increased immune response in the brain of mutant mice subsequently has an effect on neurons by inducing intraneuronal LRRK2 upregulation. However, the enhanced neuroinflammation is unlikely to be triggered by dysfunctional microglia or infiltrated T cells and/or monocytes, but by peripheral circulating inflammatory molecules. Analysis of cytokine kinetics and inflammatory pathways in the peripheral immune cells demonstrates that LRRK2 mutation alters type II interferon immune response, suggesting that this increased neuroinflammatory response may arise outside the central nervous system. Overall, this study suggests that peripheral immune signalling plays an unexpected-but important-role in the regulation of neurodegeneration in LRRK2-associated Parkinson's disease, and provides new targets for interfering with the onset and progression of the disease.

Background: MPTP and paraquat are two compounds that have been used to model Parkinson’s disease in mice. Previous studies in two non-traditional strains of mice have shown that a single dose of MPTP can induce changes in body temperature, while the effects of paraquat have not been examined. Examination of body temperature is important since small fluctuations in an animal’s core temperature can significantly affect drug metabolism, and if significant enough can even culminate in an animal’s death.Objective: To determine how external heating can alter the survival of C57BL/6J mice following MPTP administration.Methods: In this study, we examine the effects of MPTP (4×20 mg/kg, 2 hours apart) and paraquat (2×10 mg/kg/week for 3 weeks) on core temperature of C57BL/6J mice. Correlations of purine and catecholamine levels were also done in mice treated with MPTP.Results: We find that MPTP induces a significant hypothermia in C57BL/6J mice that reduces their core temperature below the limit of fatal hypothermia. Unlike MPTP, paraquat did not induce a significant hypothermia. Placement of animals on heating pads significantly abrogates the loss of core temperature. In both heated and non-heated conditions, mice treated with MPTP showed a significant depletion of ATP within 2 hours of administration in both striatum and SN that started to recover 2 hours after MPTP administration was complete. Striatal DA and DOPAC are significantly reduced starting 4–6 hours after MPTP.Conclusions: The fatal hypothermic effects of MPTP can be abrogated through use of external heating.