Aberrant CpG Methylation Mediates Abnormal Transcription of MAO-A Induced by Acute and Chronic L-3,4-Dihydroxyphenylalanine Administration in SH-SY5Y Neuronal Cells.

Abstract

L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective drug for therapy of Parkinson's disease (PD); however, long-term use of it causes serious side effects. L-dopa-induced dyskinesia (LID) has consistently been related to L-dopa-derived excessive dopamine release, but the mechanisms have not been addressed very clear. Monoamine oxidase A (MAO-A) is one of the key enzymes in dopamine metabolism and therefore may be involved in L-dopa-induced side effects. And, epigenetic modification controls MAO-A gene transcription. To investigate the effects of L-dopa on MAO-A transcription and its underlying epigenetic mechanism, neuronal SH-SY5Y cells were treated with L-dopa for 24h (acute) and for 7-21days (chronic). Results showed that chronic L-dopa administration resulted in a dose-dependent and time-dependent downregulation of MAO-A, whereas acute L-dopa administration induced upregulation of MAO-A transcription and expression. Meanwhile, chronic L-dopa exposure induced CpG hypermethylation in MAO-A promoter, while acute L-dopa administration caused CpG hypomethylation. And, CpG demethylation resulted in reactivation of MAO-A transcription. These results indicated that aberrant CpG methylation might play a key role in MAO-A transcriptional misregulation in L-dopa administration. In addition, results showed that acute L-dopa administration induced downregulation of DNA methyltransferase 3a (DNMT3a). Transcription of ten-eleven translocation 1 (TET1) were significantly downregulated in chronic L-dopa administration. These data indicated that in chronic L-dopa administration, TET1 downregulation might mediate CpG hypermethylation, which is responsible for the downregulation of MAO-A transcription. In contrast, in acute L-dopa administration, DNMT3a downregulation might mediate hypomethylation, contributing to the MAO-A upregulation. In conclusion, our findings suggested that TET1 and DNMTs might mediate aberrant CpG methylation, associated with the misregulation of MAO-A in L-dopa administration, which might contribute to dopamine release abnormally leading to the side effects of L-dopa.