Genetics of MPTP-Induced Parkinsonism

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurological disorder that strikes 20 per 100,000 persons greater than 50 years of age. It is estimated that 1 million US citizens have PD, with adults over 60 having a 1 in 20 chance of getting PD. At an average per capita cost of $6000.00 year/patient, the total cost of the disease approximates $6 billion dollars, of which 85% is borne to private and government insurance agencies. Since the population of the world is getting progressively older, the number of people suffering from this disease should substantially increase within the next several decades. The cause of >90% of all PD cases is unknown. Current hypotheses on the etiology of idiopathic PD (IPD) state that there is an interaction of some as yet unknown environmental agent with a genetic predisposition to its effects. The discovery of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) has provided a useful model of Parkinsonism that appears to recapitulate the pathology of the disease seen in man. Exposure to this prototypical "environmental toxin" causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In mice, the effects of MPTP are strain dependent. We have used a QTL analysis to demonstrate that the gene underlying strain differences is located on chromosome 1. Within this chromosomal region, one gene: glutathione-S-transferase pi2 functions within the detoxification pathway for exogenous agents. In this application, we propose to study the structure and function of this gene and its related family members. Four specific aims are proposed: 1) Determine if there are any differences in the sequence and expression of GSTp2 and related family members in MPTP-resistant and sensitive strains of mice. 2) Examine the effects of blockade or transfer of GSTpi on cell death following administration of MPTP in vitro and in vivo; 3) Develop the rotenone model of experimental Parkinsonism in mice and determine if GSTp2 is altered in response to rotenone; 4) Determine if there are structural or expression differences in GSTpi levels in humans with Parkinson's disease. The results of this study should lead to a better understanding of the pathogenesis of experimental and possible human Parkinson's disease. This identification of GSTp2 as a candidate gene could also lead to the identification of diagnostic measures and point to potential therapies for early intervention in this devastating illness.