1-Methyl-4-phenyl-pyridinium increases S-adenosyl-L-methionine dependent phospholipid methylation

1-Methyl-4-phenyl-pyridinium (MPP+) and S-adenosyl-L-methionine (SAM) cause Parkinson's disease (PD)-like changes. SAM and MPP+ require their charged S-methyl and N-methyl groups, so the PD-like symptoms may be related to the ir ability to modulate the methylation process. The SAM-dependent methylati on of phosphatidylethanolamine (PTE) to produce phosphatidylcholine (PTC), via phosphatidylethanolamine-N-methyltransferase (PEMT), and the hydrolysis of PTC to form lyso-PTC, a cytotoxic agent, are potential loci for the act ion of MPP+. In this study, the effects of MPP+ on the methylation of PTE t o PTC and the production of lyso-PTC were determined. The results showed th at SAM increased PTC and lyso-PTC. The rat striatum showed the highest PEMT activity and lyso-PTC formation, which substantiate with the fact that the striatum is the major structure that is affected in PD. MPP+ significantly enhanced PEMT activity and the formation of lyso-PTC in the rat liver and brain. MPP+ increased the affinity and the V-max of PEMT for SAM. I Methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effect was lesser and inhibited by deprenyl (MAO-B inhibitor). The nor-methyl analogs of MPP+ were inactive , but some of the charged analogs of MPP+ showed comparable effects to thos e of MPP+. Lyso-PTC that can be increased by SAM and MPP+ caused severe imp airments of locomotor activities in rats. These results indicate that SAM a nd MPP+ have complementary effects on phospholipid methylation. Thus, SAM-i nduced hypermethylation could be involved in the etiology of PD and an incr ease of phospholipid methylation could be one of the mechanisms by which MP P+ causes parkinsonism. (C) 2001 Elsevier Science Inc. All rights reserved.