The role of phospholipid methylation in 1-methyl-4-phenyl-pyridinium ion (MPP+)-induced neurotoxicity in PC12 cells.
Excessive methylation has been proposed to be involved in the pathogenesis of Parkinson's disease (PD), via mechanisms that involve phospholipid methylation. Meanwhile, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to stimulate phospholipid methylation via the oxidized metabolite, 1-methyl-4-phenyl-pyridinium (MPP+), in the rat brain and liver tissues. In the present study, we investigated the effect of MPP+ on phosphatidylethanolamine N-methyltransferases (PENMT) and the potential role of this pathway in MPP(+)-induced neurotoxicity using PC12 cells. The results obtained indicate that MPP+ stimulated phosphatidylethanolamine (PTE) methylation to phosphatidylcholine (PTC) and correspondingly increased the formation of lysophosphatidylcholine (lyso-PTC). Moreover, the addition of S-adenosylmethionine (SAM) to the cell culture medium increases MPP(+)-induced cytotoxicity. The incubation of 1mM MPP+ and various concentrations of SAM (0-4 mM) decreased the viability of PC12 cells from 80% with MPP+ alone to 38% viability with 4 mM SAM for 4 days incubation. The data also revealed that the addition of S-adenosylhomocysteine (SAH), a methylation inhibitor, offered significant protection against MPP(+)-induced cytotoxicity, indicating that methylation plays a role in MPP(+)-induced cytotoxicity. Interestingly, lyso-PTC showed similar actions to MPP+ in causing many cytotoxic changes with at least 10 times higher potency. Lyso-PTC induced dopamine release and inhibited dopamine uptake in PC12 cells. Lyso-PTC also caused the inhibition of mitochondrial potential and increased the formation of reactive oxygen species in PC12 cells. These results indicate that phospholipid methylation pathway might be involved in MPP+ neurotoxicity and lyso-PTC might play a role in MPP(+)-induced neurotoxicity.
Lee
Eun-Sook Y
ES
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. eunsook.lee@famu.edu
Chen
Hongtao
H
Charlton
Clivel G
CG
Soliman
Karam F A
KF
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000096:biosynthesis* / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D016716:PC12 Cells; D010713:Phosphatidylcholines / Q000096:biosynthesis; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000187:drug effects* / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000494:pharmacology
D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; C483858:phosphatidylethanolamine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D050918:Phosphatidylethanolamine N-Methyltransferase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine