α-Synuclein Up-regulates Monoamine Oxidase A Expression and Activity via Trans-Acting Transcription Factor 1

Congcong Jia; Cheng Cheng; Tianbai Li; Xi Chen; Yuting Yang; Xinyao Liu; Song Li; Weidong Le

doi:10.3389/fnagi.2021.653379

α-Synuclein Up-regulates Monoamine Oxidase A Expression and Activity via Trans-Acting Transcription Factor 1

Front Aging Neurosci. 2021 Mar 17:13:653379. doi: 10.3389/fnagi.2021.653379. eCollection 2021.

Authors

Congcong Jia^{1

2}, Cheng Cheng^{1

2}, Tianbai Li^{1

2}, Xi Chen^{1

2}, Yuting Yang^{1

2}, Xinyao Liu^{1

2}, Song Li^{1

2}, Weidong Le^{1

2

3}

Affiliations

¹ Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
² Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
³ Department and Institute of Neurology, Sichuan Academy of Medical Sciences, Sichuan Provincial Hospital, Chengdu, China.

Abstract

Abnormal α-Synuclein (α-SYN) aggregates are the pathological hallmarks of Parkinson's disease (PD), which may affect dopamine (DA) neuron function and DA metabolism. Monoamine oxidase A (MAOA) is an enzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of DA. Both α-SYN and MAOA are associated with PD pathogenesis, suggesting possible crosstalk between these two molecules. In the present study, we aimed to investigate the potential impacts of α-SYN on MAOA function and further explore the underlying mechanisms. Our study showed that overexpression of α-SYN [both wild-type (WT) and A53T] increased MAOA function via upregulating its expression without impacting MAOA stability. Overexpression of α-SYN^WT or α-SYN^A53T enhanced the transcription activity of the MAOA promoter region containing the binding sites of cell division cycle associated 7 like (R1, a transcriptional repressor of MAOA) and trans-acting transcription factor 1 (Sp1, a transcription factor of MAOA). Interestingly, α-SYN selectively increased Sp1 expression, thereby enhancing the binding capacity of Sp1 with MAOA promoter to increase MAOA expression. Taken together, our findings demonstrate that α-SYN can upregulate MAOA expression via modulation of Sp1 and may shed light on future studies of α-SYN associated PD pathogenesis.

Keywords: MAOA; Parkinson’s disease; Sp1; dopamine; α-Synuclein.