Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y₁₂-receptor (P2Y₁₂R), which is expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y₁₂R in PD is unknown. Here we show that MPTP-induced PD symptoms in mice are associated with marked neuroinflammatory changes and P2Y₁₂R contribute to the activation of microglia and progression of the disease. Surprisingly, while pharmacological or genetic targeting of the P2Y₁₂R augments acute mortality in MPTP-treated mice, these interventions protect against the neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y₁₂R regulates ROCK and p38 MAPK activity and control cytokine production. Our principal finding is that the receptor has a dualistic role in PD: functional P2Y₁₂Rs are essential to initiate a protective inflammatory response, since the lack of the receptor leads to reduced survival; however, at later stages of neurodegeneration, P2Y₁₂Rs are apparently responsible for maintaining the activated state of microglia and stimulating pro-inflammatory cytokine response. Understanding protective and detrimental P2Y₁₂R-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

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