title: 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 24 h (acute) and for 7-21 days (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.
authors.affiliation: Department of Neurobiology, Capital Medical University, Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China.|Center for Clinical Research on Neurological Diseases, 1st Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Physiology, Capital Medical University, Key Laboratory for Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Capital Medical University, Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Physiology, Capital Medical University, Key Laboratory for Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China. kingwyong@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Capital Medical University, Key Laboratory for the Neurodegenerative Disorders of the Chinese Ministry of Education, and Beijing Institute for Brain Disorders, 10# You An Men, Beijing, 100069, China. xmwang@ccmu.edu.cn.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004295:Dihydroxyphenylalanine / Q000008:administration & dosage* / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008995:Monoamine Oxidase / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D004295:Dihydroxyphenylalanine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D008995:Monoamine Oxidase; D000090205:DNA Methyltransferase 3A
keywords: CpG island methylation; L-3,4-dihydroxyphenylalanine; Monoamine oxidase A (MAO-A); Ten-eleven translocation 1 (TET1)