PARKINSONISM AND MPP+ --A METHYL-DONOR ACTION FOR MPP+

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One-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPP+) and 1-methyl-4- phenylpyridinium (Mpp+) caused Parkinson's disease (PD)-like symptoms. Recently, it was observed that the injection of excess S- adenosylmethionine (SAM) in the brain of rodents also caused PD-like effects. SAM is the endogenous methyl donor and requires the S-methyl group for its activity. MPTP and MPP+ also require their N-methyl groups for their activities. Therefore, like SAM, MPP+, which is the active metabolite of MPTP, may serve as a methyl donors. This idea is enhanced by the fact that the ionic state of MPP+ favors its action as a methyl donor. In our laboratory we found that MPP+, but not MPTP, can donate a methyl group to dopamine (DA), which shows that MPP+ can serve as a methyl donor. Such an effect may be related to the direct action of MPP+ and the lack of direct action of MPTP. As a methyl donor, it means also that, like SAM, MPP+ may methylate phospholipids (PL) and proteins. The methylation of PL and proteins may disrupt cell membranes, affecting exocytosis and other functions, which along with the methylation of other cellular constituents, e.g. dopamine (DA) may underlie the toxicity of MPP+. In this project the ability of MPTP, MPP+ and SAM to serve as methyl donors for DA, PL and proteins will be studied and compared. The methods will involve in vitro assays, using partially purified COMT, and HPLC methods, to determine the ability of MPTP, MPP+ and SAM to methylate DA. The methylation of PL and proteins will be studied in brain cell membranes, cytosol and synaptosomes. The PL will be characterized using TLC. Antagonists to MPP+ methylation and the effects of MPP+ on SAM- dependent methylation will also be determined. In addition, the effect of MPTP, MPP+ and SAM on the release of DA will be compared with their ability to methylate DA, PL and proteins. If the role of a general methyl donor can be substantiated for MPP+ the results will constitute a significant finding that will help us to know more about PD as well as aging and cell longevity, because there is a close interrelationship between aging, PD, cell longevity and the action of MPP+. Methylation is tightly regulated, in part, by the limiting existence of SAM. The identification of a stable methyl donor (MPP+) will add a new rational biochemical approach and will generate much impetus in the study of the MPTP class of compounds, PD and methylation; noting that methylation is involved in the regulation of important biomolecules--including nucleic acids, proteins, lipids, carbohydrates, monoamines, acetylcholine--as well as regulatory function, e.g. transcriptional silence, aging, exocytosis, biogenicamines regulation and membrane biophysics.