Prostaglandin E2 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 E2 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-/-) 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-/- 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.


CONCLUSIONS
Thus, it appears that microglial EP2 plays a critical role in alpha-synuclein-mediated neurotoxicity.
Jin
Jinghua
J
Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. jinj@u.washington.edu <jinj@u.washington.edu>
Shie
Feng-Shiun
FS
Liu
Jun
J
Wang
Yan
Y
Davis
Jeanne
J
Schantz
Aimee M
AM
Montine
Kathleen S
KS
Montine
Thomas J
TJ
Zhang
Jing
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051844:alpha-Synuclein / Q000502:physiology / Q000633:toxicity*
C545644:PTGER2 protein, human; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine