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

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-SYNWT or α-SYNA53T 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.

Elevated Monoamine Oxidase-A in Anterior Cingulate of Post-Mortem Human Parkinson’s Disease: A Potential Surrogate Biomarker for Lewy Bodies?

“…Although α-synuclein aggregates have been suggested to be involved in LB formation [ 36 , 37 ], more careful assessment of α-synuclein aggregate distribution in the anterior cingulate will have to be carried out in order to establish such links in the UIHC. However, α-synuclein may have a role in upregulating MAO-A; as suggested [ 8 ], the distribution of MAO-A appears to correlate more strongly with UIHC.…”

“…Many proteins, α-synuclein fibrils and aggregates, and macrophages are known to be present in LB and are encircled by mitochondria ( Figure 1 ). Monoamine oxidase-A, present in the outer layers of the mitorchondria, may play a significant role in the pathogenesis of neurodegeneration causing neurotransmitter breakdown, increased production of reactive oxygen species and possible roles in microglia activation and inflammation [ 8 , 34 ].…”

“…Upregulation of MAO-A expression due to α-synuclein aggregates has been reported [ 8 ]. MAO-A inhibitors are used as a treatment for affective disorders [ 9 ].…”

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies

“…Rasagiline and MAO-B knockout could prevent the toxicity and inhibition of the AEP/MAO-B pathway, which might be another mechanism of the neuroprotection by rasagiline [ 172 ]. Overexpression of wild type and A53T αSyn upregulated MAO-A protein expression by selective induction of Sp1, a transcription factor of MAO-A, and promoted depressive-like behaviors in mice [ 174 , 175 ]. The impairment of MAO-A by αSyn may be associated with depression in PD.…”

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

“…The authors found that DOPAL strongly activates asparagine endopeptidase, and the N103 fragment of αS binds and activates MAO-B, which could result in a lethal positive feedback loop. Jia et al recently reported that αS up-regulates MAO-A [ 140 ].…”