NT5DC2 downregulation suppresses monoamine oxidase activity and promotes catecholamine synthesis in PC12D cells

Background: Genome-wide association studies have revealed the involvement of 5ʹ-nucleotidase domain-containing protein 2 (NT5DC2) in neuropsychiatric disorders such as schizophrenia and bipolar disorder; however, its function remains unclear. We recently found that NT5DC2 downregulation in PC12D cells increases catecholamine synthesis by promoting tyrosine hydroxylase (TH) activity. In addition, affinity purification–mass spectrometry suggested a potential interaction between NT5DC2 and monoamine oxidase A (MAO A). In this study, we examined the impact of NT5DC2 on MAO A activity in PC12D cells and the related effects on catecholamine metabolism. Methods and results: We analyzed changes in catecholamine metabolism in siRNA-mediated NT5DC2-downregulated PC12D cells by measuring the catecholamines and major acid metabolites produced by the addition of exogenous dopamine (DA) to PC12D cells, with DOPA synthesis suppressed by the addition of a TH inhibitor. Western blot analysis revealed that NT5DC2 primarily binds to the non-phosphorylated form of MAO A. NT5DC2 downregulation reduced MAO A activity, leading to decreased dopamine metabolism and increased noradrenaline synthesis. Conclusion: Our findings suggest that NT5DC2 regulates MAO A activity to control catecholamine synthesis. This study provides valuable insights into disorders associated with catecholamine dysregulation, such as Parkinson’s disease and neuropsychiatric disorders.