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Background  The pathogenesis of idiopathic Parkinson's disease (PD) remains elusive, although evidence has suggested that neuroinflammation characterized by activation of resident microglia in the brain may contribute significantly to neurodegeneration in PD. It has been demonstrated that aggregated α-synuclein potently activates microglia and causes neurotoxicity. However, the mechanisms by which aggregated α-synuclein activates microglia are not understood fully.    Methods  We investigated the role of prostaglandin E 2  receptor subtype 2 (EP2) in α-synuclein aggregation-induced microglial activation using  ex vivo, in vivo and in vitro  experimental systems.    Results  Results demonstrated that ablation of EP2(EP2 -/- ) significantly enhanced microglia-mediated  ex vivo  clearance of α-synuclein aggregates (from mesocortex of Lewy body disease patients) while significantly attenuating neurotoxicity and extent of α-synuclein aggregation in mice treated with a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Furthermore, we report that reduced neurotoxicity by EP2 -/-  microglia could be attributed to suppressed translocation of a critical cytoplasmic subunit (p47-phox) of NADPH oxidase (PHOX) to the membranous compartment after exposure to aggregated α-synuclein.    Conclusion  Thus, it appears that microglial EP2 plays a critical role in α-synuclein-mediated neurotoxicity.

Prostaglandin E2 receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by aggregated α-synuclein