Parkinson's disease (PD) is a common movement disorder with tremor, rigidity, and bradykinesia. The central event in PD is the loss of the dopaminergic inputs to the basal ganglia. The disease is characterized by great variability from patient to patient in the course of the disease, the relative predominance of various symptoms, the response to L-DOPA therapy, and the development of dyskinesias during L-DOPA therapy. Studies exploring the ramifications of the dopamine deficiency in PD have provided increasing evidence that changes in the other basal ganglia neurotransmitter systems, in particular the opioid system, may also play a role in the disease process. This evidence includes PET scan studies in PD patients that showed correlations between dyskinesias and altered opioid binding levels, as well as work in animal models sugggesting the involvement of opioid system in the development of dyskinesias during L-DOPA therapy. In this revised application, the basic hypothesis we propose to test is that some of the observed variability in PD patient's symptoms and response to L-DOPA may be related to an underlying genetic variation in opioid receptors. We propose to study genetic polymorphism of the mu opioid receptor in PD patients, and to characterize at a cellular level the consequences of these polymorphisms on receptor expression level and receptor function.
The specific aims of the proposal are: 1. To identify genetic polymorphisms in both the promoter and the coding region of the mu opioid receptor in PD patients and to determine whether any of the polymorphisms are associated with variations in clinical symptoms and outcomes: 2.) To determine the effect of the coding region polymorphisms on both ligand binding properties of the receptor and receptor-mediated cellular functions; and 3.) To determine the effect of promoter sequence polymorphisms on the expression levels of the receptor. Such functional studies are essential in moving from association to causality. Our preliminary studies of 26 PD patients have identified a mu opioid receptor polymorphism in the PD population. This polymorphism was significantly associated with the clinical outcome of L-DOPA therapy-induced dyskinesia. Further studies in a larger PD patient cohort may identify additional polymorphisms of interest, and may provide predictor for clinical management of PD.
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