Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson's Disease

BACKGROUND: Mechanisms whereby gene-environment interactions mediate chronic, progressive neuro degenerative processes in Parkinson's disease (PD)-the second most common neuro-degenerative disease-remain elusive. OBJECTIVE: We created a two-hit [neuro inflammation and mutant alpha-synuclein (alpha-syn) overexpression] animal model to investigate mechanisms through which mutant alpha-syn and inflammation work in concert to mediate chronic PD neuro degeneration. METHODS: We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 x 10(6) EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice over expressing human A53T mutant alpha-syn. We then evaluated nigral dopaminergic neurodegeneration, alpha-syn pathology, and neuro inflammation. RESULTS: After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuro inflammation; however, only Tg mice developed persistent neuro inflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated alpha-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical-generating enzymes in activated microglia, blocked nigral alpha-syn pathology and neuro degeneration in LPS-injected Tg mice. CONCLUSIONS: Microglia-derived oxidative stress bridged neuro inflammation and alpha-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neuro degeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression.