Gangliosides in Podocyte Biology and Disease

Abstract

Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis, ganglioside synthases, and their degradation, glycosidases. The dysregulation of their abundance results in rare and common diseases. In this review, we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.

Keywords: ceramide; glomerulopathies; glomerulus; glycosphingolipids; kidney; nephrotic syndrome; podocytopathies; rafts.

Figure 1

Global view of the sphingolipid metabolism. Simplified representation of the four main pathways encompassing the synthesis of sphingolipid species, with ceramides as central compounds. Plain arrows indicate single reactions. Dashed arrows denote multiple reactions. De novo and sphingomyelin pathways result in ceramide synthesis from palmitic acid and sphingomyelin as ultimate precursors, respectively. The so-called salvage or catabolic pathway results in the production of the bioactive sphingosine-1 phosphate. Ceramide itself can be phosphorylated into the bioactive ceramide-1 phosphate. Finally, the hydrolytic or glycosphingolipid pathway leads to ceramide glycation. Galactosyl-ceramide is the precursor of sulfatides, not shown in the figure. The rest of the complex glycosphingolipids (lactosides, globosides, cerebrosides, and gangliosides) are derived from lactosyl ceramide (LacCer). All pathways are reversible except the de novo synthesis.

Figure 2

Schematic representation of ganglioside biosynthesis pathways. LacCer are the precursors of the globo, lacto, muco, and ganglio series of glycosphingolipids. GM3 are the precursors of the a, b, and c series of gangliosides. LacCer are precursors of asialo (0-series) gangliosides (GA). GA1 give way to fucosylated glycosphingolipids. “/” denotes two different structures of gangliosides produced from the same precursor. “α” denotes specific ganglioside structures in which one sialic acid residue is branched to N-acetylgalactosamine (GalNAc). All the other sialic acid residues are branched to galactose residues (modified from [5]). The orange colored rectangles denote the molecular species whose abundance has been reported to date as changed in the context of podocytopathies (summarized in Table 1). Many of these reactions are reversible. GM: Monosialo gangliosides; GD: Disialo gangliosides; GT: Trisialo gangliosides; GQ: Quadrisialo gangliosides; GP: Pentasialo gangliosides.