MOLECULAR GENETIC ANALYSIS OF S ADENOSYL L METHIONINE IN PARKINSONS DISEASE

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Parkinson's diseases (PD) is a neurodegenerative disorder characterized by the loss of control of a variety of motor functions. The major markers of PD have been the degeneration of dopamine-containing cell bodies in the brain and the loss of the neurotransmitter dopamine (DA). Establishing a molecular basis for nigrostriatal neuronal degradation and the decrease in DA production is pivotal to developing potent, selective agents for therapeutic intervention in PD. Recent in vivo studies have implicated S- adenosyl-L-methionine (SAM) in the pathophysiology of PD. Injection of SAM into the brain of rats induces pathological and behavioral changes that resemble those observed in PD patients. The pathological changes include degradation of neurons in the substantia nigra. Preliminary data indicate that following SAM treatment, degeneration of tyrosine hydroxylase (TH)- containing fibers is observed and this is accompanied by a decrease in substantia nigra TH immunoreactivity. These results suggest that SAM might be modulating the expression of TH, the enzyme which catalyzes the rate- limiting step for DA biosynthesis. If this is the case, then elevation of SAM in the brain could trigger changes in TH gene expression, which in turn might lead to DA depletion and neuronal cell degenerations. The project will utilize a molecular approach to investigate the possible effects of SAM on TH gene expression. Brain tissue homogenates from SAM-treated and control rats will be analyzed for TH mRNA levels using an RT-PCR method. Modulation of TH mRNA transcription by SAM could suggest that TH is involved in SAM-induced DA depletion. Immunochemical studies will also be carried out to determine whether SAM also affects TH mRNA translation. Results obtained from these studies will provide insights into the mechanism of SAM's action in depleting DA in the rat model for PD.