Methylglyoxal Affects Dopamine Homeostasis in SH-SY5Y Cells Through the Modulation of miR-190a and miR-214

: Dopamine (DA) homeostasis is crucial for several relevant body functions, including cognition. Diabetes mellitus (DM) is characterized by both cognitive decline and dopaminergic dysfunction. Methylglyoxal (MGO), a reactive neurotoxic dicarbonyl, which accumulates in DM, induces dopaminergic dysfunction, contributing to DA depletion, and is associated with cognitive deficit. However, the molecular mechanisms underlying MGO impact on dopaminergic function are still unknown. This study aims to clarify how MGO damages the dopaminergic system, analyzing the contribution of miRNAs in its deleterious effect in SH-SY5Y cells. We found that treatment with MGO significantly reduces the intracellular DA content, increasing the expression of proteins known to negatively affect DA amount, such as COMT (Catechol-O-methyltransferase), MAO (Monoamine oxidase), and α-Syn (α-synuclein), encoded by the SNCA gene. This was paralleled by a significant reduction in the expression of miR-190a and miR-214, known to be regulated by MGO in other cellular models. We found, by TARGETSCAN analysis, that these two miRNAs are predicted regulators of COMT and SNCA. Gain- and loss-of-function experiments highlighted that these miRNAs are able to modulate the expression of these proteins. We also showed that COMT is a direct target of both miR-190a and miR-214, while SNCA is a direct target of miR-190a and an indirect target for miR-214. Importantly, the transfection of miR-190a and miR-214 specific mimics reverted MGO effects on COMT and α-Syn expression and restored DA intracellular content. Thus, these miRNAs could represent innovative pharmacological targets for the treatment of DM-associated dopaminergic dysfunction and cognitive decline.