Prostaglandin E sub(2 )receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by aggregated alpha -synuclein

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 alpha -synuclein potently activates microglia and causes neurotoxicity. However, the mechanisms by which aggregated alpha -synuclein activates microglia are not understood fully. Methods We investigated the role of prostaglandin E sub(2 )receptor subtype 2 (EP2) in alpha -synuclein aggregation-induced microglial activation using ex vivo, in vivo and in vitro experimental systems. Results Results demonstrated that ablation of EP2(EP2 super(-/-)) significantly enhanced microglia-mediated ex vivo clearance of alpha -synuclein aggregates (from mesocortex of Lewy body disease patients) while significantly attenuating neurotoxicity and extent of alpha -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 super(-/- )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 alpha -synuclein. Conclusion Thus, it appears that microglial EP2 plays a critical role in alpha -synuclein-mediated neurotoxicity.