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

Abstract

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.

CONCLUSION:

Thus, it appears that microglial EP2 plays a critical role in alpha-synuclein-mediated neurotoxicity.

• Authors: Jinghua Jin, Feng-Shiun Shie, Jun Liu, Yan Wang, Jeanne Davis, Aimee M Schantz, Kathleen S Montine, Thomas J Montine, Jing Zhang
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 4 Pg. 2 (Jan 04 2007) ISSN: 1742-2094 [Electronic] England
• PMID: 17204153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• PTGER2 protein, human
• Ptger2 protein, mouse
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP2 Subtype
• alpha-Synuclein
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)
• Animals
• Humans
• Lewy Body Disease (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Microglia (drug effects, metabolism)
• Receptors, Prostaglandin E (physiology)
• Receptors, Prostaglandin E, EP2 Subtype
• alpha-Synuclein (physiology, toxicity)