Calcium Overloading-Induced UBE2O Upregulation Alleviates Neuronal Apoptosis

Calcium overloading is implicated in the pathogenesis of Alzheimer's Disease (AD) via the activation of calcineurin signaling. Dysregulation of ubiquitin-conjugating enzyme E2 O (UBE2O), an E2-E3 hybrid enzyme, is involved in AD pathogenesis. However, the effect of calcium overloading-mediated calcineurin activation on UBE2O regulation and the role of UBE2O in calcium overloading-induced apoptosis remain elusive. In this study, we aimed to explore the effect of calcium overloading on UBE2O expression and underlying mechanisms, as well as its role in apoptosis. We found that calcium overloading increases the expression of UBE2O in both neuronal and non-neuronal cells, while calcineurin inhibitor alleviates this effect. Moreover, three functional binding sites of MEF2A, a downstream target of calcineurin, are identified within the promoter region of the UBE2O gene. MEF2A facilitates UBE2O promoter activity, as well as its expression at both mRNA and protein levels. Furthermore, increased UBE2O expression attenuates calcium overloading-induced neuronal apoptosis, while reduced UBE2O expression exacerbates calcium overloading-induced neuronal apoptosis. Moreover, neuron-specific overexpression of UBE2O reduced neuronal apoptosis in 5 × FAD mice. This study demonstrated that calcium overloading-induced UBE2O upregulation is mediated by calcineurin-MEF2A signaling pathway, which acts as a protective response to alleviate neuronal apoptosis. It indicates that UBE2O is a potential therapeutic target for neuronal protection in AD.