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

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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.

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Acknowledgments

This work was supported by the National Basic Research Program of the China-973 Project (2011CB504100 and 2006CB500700), the Natural Science Foundation of Beijing Municipality (7082008), and the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges under Beijing Municipality (IDHT20140514). We thank Professor Quangen Zhang in Capital Medical University for kindly gifting antibody of DNMT1.

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Authors and Affiliations

  1. 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

    Zhaofei Yang, Jian Yang, Min Sun & Xiaomin Wang

  2. Center for Clinical Research on Neurological Diseases, 1st Affiliated Hospital, Dalian Medical University, Dalian, China

    Zhaofei Yang

  3. 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

    Xuan Wang & Yong Wang

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  1. Zhaofei Yang
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  2. Xuan Wang
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  3. Jian Yang
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  4. Min Sun
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Supplementary Figure 1

Effects of chronic l-dopa administration on cell viability of human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with l-dopa (0 μM, 2 μM and 20 μM) for 7 d, 14 d and 21 d. Cell viability was measured by cell counting with Trypan Blue staining. l-dopa at 20 μM induced significantly decreased cell viability, compared to control. The values represent the means ± SEM (n = 4). ***P < 0.001 vs. ctr. ctr: control; L2: 2 μM of l-dopa; L20: 20 μM of l-dopa. (GIF 45 kb)

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Yang, Z., Wang, X., Yang, J. et al. Aberrant CpG Methylation Mediates Abnormal Transcription of MAO-A Induced by Acute and Chronic l-3,4-Dihydroxyphenylalanine Administration in SH-SY5Y Neuronal Cells. Neurotox Res 31, 334–347 (2017). https://doi.org/10.1007/s12640-016-9686-5

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