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First published on June 27, 2007; DOI: 10.1124/mol.107.038158

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Received for publication May 17, 2007.
Revised June 27, 2007.
Accepted for publication June 27, 2007.

Exacerbation of dopamine terminal damage in a mouse model of Parkinson's disease by the G-protein coupled receptor, PAR1

Cecily E. Hamill 1, W. Michael Caudle 1, Jason R. Richardson 1, Hongjie Yuan 1, Kurt D. Pennell 2, James G. Greene 1, Gary W. Miller 1, Stephen F. Traynelis 1*

1 Emory University 2 Georgia Institute of Technology

* Address correspondence to: E-mail: strayne{at}emory.edu

Abstract

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. Following MPTP injection, PAR1-/- mice showed significantly higher residual levels of dopamine, dopamine transporter, tyrosine hydroxylase, and diminished microgliosis compared to 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. microgliosis compared to wild-type mice. Comparable levels of dopaminergic neuroprotection from MPTP-induced toxicity were obtained by infusion of the PAR1 antagonist, BMS200261. 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.


Key words: Dopamine, Gi family, Gq/11 family, G12,13;other G's, Oxidative stress, Excitotoxicity, neurodegeneration




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