S-adenosymethionine (SAM), the biological methyl donor, causes tremor, rigidity and hypokinesia in rodents. These changes are inhibited by L-dopa, but not D-dopa. SAM also destroys nigrostriatal (NS) dopamine (DA) neurons, causes DA and tyrosine hydroxylase depletion, metabolizes norepinephrine and serotonin, increases acetylcholine, and by shunting tyrosine to the methylation pathway SAM can also decrease melanin. These changes also occur in PD. The cause of PD and the mechanisms by which SAM induces the PD-like changes are unknown, but three hypotheses will be explored that will help to explain the neurotoxic effects of SAM, and this may illuminate the cause of idiopathic PD. Firstly, SAM methylates and depletes nigrostriatal DA, and this eventually leads to the biochemical malfunction of DA neuronal processes and neuronal degeneration. Secondly, SAM methylates membrane phosphatidylethanolamine, produces phosphatidylcholine (PTC) and induces phospholipases, which increases lyso-PTC. Lyso-PTC is cytotoxic. Free diacylglycerol (DAG), arachidonic acid (AA), phosphatidic acid and phosphorylcholine are also produced with potentially neuropathological consequences. Finally, the utilization of SAM increases the levels of excitotoxin, homocysteine (HC) and also adenosine, which has been shown to be antagonistic to the action of DA. The goal of this application is to inquire whether an increase synthesis and utilization (increase activity) of SAM results in the methylation of DA and phospholipids (PL) in the brain, increases HC, produces toxic metabolites, impairs DA neuronal processes and causes neuronal degeneration. The results will help to determine whether methylation, which increases during aging, leads to neuronal damage, may induce PD-like symptoms in susceptible individuals and may be the link between aging and parkinsonism. Indeed, the information generated will set the stage for further basic studies and clinical investigations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Oliver, Eugene J
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Florida Agricultural and Mechanical University
Schools of Pharmacy
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