QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.107.038158v1 72/3/653    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hamill, C. E. Articles by Traynelis, S. F. Search for Related Content PubMed PubMed Citation Articles by Hamill, C. E. Articles by Traynelis, S. F.

Exacerbation of Dopaminergic Terminal Damage in a Mouse Model of Parkinson's Disease by the G-Protein-Coupled Receptor Protease-Activated Receptor 1

Departments of Pharmacology (C.E.H., H.Y., S.F.T.) and Neurology (J.G.G.), and Center for Neurodegenerative Disease (C.E.H., W.M.C., J.R.R., G.W.M.), Emory University School of Medicine, and Department of Environmental and Occupational Health, Emory University Rollins School of Public Health (W.M.C., J.R.R., G.W.M.), Atlanta, Georgia; and Department of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia (K.D.P.)

Protease-activated receptor 1 (PAR1) is a G-protein-coupled receptor activated by serine proteases and expressed in astrocytes, microglia, and specific neuronal populations. We examined the effects of genetic deletion and pharmacologic blockade of PAR1 in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease, a neurodegenerative disease characterized by nigrostriatal dopamine damage and gliosis. After MPTP injection, PAR1–/– mice showed significantly higher residual levels of dopamine, dopamine transporter, and tyrosine hydroxylase and diminished microgliosis compared with wild-type mice. Comparable levels of dopaminergic neuroprotection from MPTP-induced toxicity were obtained by infusion of the PAR1 antagonist, BMS-200261 into the right lateral cerebral ventricle. MPTP administration caused changes in the brain protease system, including increased levels of mRNA for two PAR1 activators, matrix metalloprotease-1 and Factor Xa, suggesting a mechanism by which MPTP administration could lead to overactivation of PAR1. We also report that PAR1 is expressed in human substantia nigra pars compacta glia as well as tyrosine hydroxylase-positive neurons. Together, these data suggest that PAR1 might be a target for therapeutic intervention in Parkinson's disease.

Address correspondence to: Stephen F. Traynelis, Department of Pharmacology, Emory University School of Medicine, 5025 Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322. E-mail: strayne{at}emory.edu