Sialic acids are terminal acidic monosaccharides that affect the chemical and structural properties of glycoconjugates, and ultimately modulate their activity in various biological processes. Sialic acids can be removed from glycoconjugates by sialidases, a family of hydrolytic enzymes widely distributed in vertebrates and various microorganisms. Among them, four types of mammalian sialidases have been identified, which have different subcellular localization and substrate specificity.
Our research group has been involved in understanding the physiological role of the membrane-bound sialidase Neu3, which is often referred to as the “ganglioside sialidase” due to its ability to strictly modulate the cellular content of gangliosides. Actually, Neu3 was first characterized because of its involvement in pathological conditions, especially in tumors, where its aberrant expression is responsible for neoplastic transformation and tumor progression. However, Neu3 is a highly conserved protein, and over the years we have elucidated its involvement in several critical processes, such as muscle differentiation and cell protection from hypoxic stress. In particular, we showed that induced down-regulation of Neu3 in skeletal muscle myoblasts completely inhibits their ability to differentiate into myotubes, whereas induced up-regulation of NEU3 during skeletal muscle differentiation activates this process and ultimately protects myoblasts from apoptosis. Furthermore, we showed that Neu3 overexpressing skeletal muscle myoblasts were more resistant to hypoxia. This led to the identification of a novel Neu3-driven mechanism of HIF-1-activation. Along this line, we found upregulation of Neu3 expression under chronic hypoxia in cyanotic congenital heart patients.
Recently, we investigated a possible role of Neu3 in mediating the cardiac cell response to ischemia and reperfusion injury (IRI). Here, we demonstrated that induced activation of Neu3 can counteract the deleterious effects of IRI on cardiac cells and ultimately increase their resistance to apoptosis by activating the RISK pathway. Overall, our data support the idea that triggering Neu3 may represent a novel approach to improve and support current strategies for the treatment of ischemic diseases, such as myocardial infarction and stroke.