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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease pathologically characterized by progressive loss of dopamine (DA) neurons in the striatum and substantia nigra (Lees et al, 2009)
The results showed that overexpression of α-SYN induced 26% and 32% DA reduction for WT and at position 53 to Thr (A53T) respectively, compared with control groups (p < 0.01, Figure 1A)
We detected the expression levels of several key proteins associated with DA metabolism, including Monoamine oxidase A (MAOA), MAOB, alcohol dehydrogenase (ADH), and catechol O-methyltransferase (COMT)
Summary
Parkinson’s disease (PD) is a neurodegenerative disease pathologically characterized by progressive loss of dopamine (DA) neurons in the striatum and substantia nigra (Lees et al, 2009) Genetic alterations, such as the reduction or mutation of genes, can cause familial forms of PD (Kalia and Lang, 2015). Α-SYN accumulation is associated with tau spreading synaptic vesicles, autophagy, mitochondria, endoplasmic reticulum and Golgi complex, nucleus, cell-to-cell propagation, and neuroinflammation related functions (Wong and Krainc, 2017; Bassil et al, 2021). All these findings indicate the important functions of α-SYN in PD pathogenesis
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