Emerging concepts of ganglioside metabolism

Abstract

Gangliosides (GGs) are sialic acid-containing glycosphingolipids (GSLs) and major membrane components enriched on cellular surfaces. Biosynthesis of mammalian GGs starts at the cytosolic leaflet of endoplasmic reticulum (ER) membranes with the formation of their hydrophobic ceramide anchors. After intracellular ceramide transfer to Golgi and trans-Golgi network (TGN) membranes, anabolism of GGs, as well as of other GSLs, is catalyzed by membrane-spanning glycosyltransferases (GTs) along the secretory pathway. Combined activity of only a few promiscuous GTs allows for the formation of cell-type-specific glycolipid patterns. Following an exocytotic vesicle flow to the cellular plasma membranes, GGs can be modified by metabolic reactions at or near the cellular surface. For degradation, GGs are endocytosed to reach late endosomes and lysosomes. Whereas membrane-spanning enzymes of the secretory pathway catalyze GSL and GG formation, a cooperation of soluble glycosidases, lipases and lipid-binding cofactors, namely the sphingolipid activator proteins (SAPs), act as the main players of GG and GSL catabolism at intralysosomal luminal vesicles (ILVs).

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

“…Surfaces of mammalian neurons are enriched in GGs of the a-and b-ganglio-series (e.g., GM1a, GD1a, GD1b, GT1a, GT1b, and polysialo-GGs), carrying up to six sialic acid residues [9]. Desialylation of complex polysialo-GGs to eventually generate GG GM1 is catabolized mainly by three membrane-bound sialidases with overlapping substrate specificities and differing subcellular location, neuraminidase NEU1, NEU3, and NEU4 [42][43][44].…”

“…generating the respective asialo-derivatives, GA1 and GA2, which are further catabolized by lysosomal hexosaminidases and β-galactosidases. Therefore, Hex A deficient mice avoid a major glycolipid accumulation and are a poor model of TSD [9,35]. They keep a slow GM2 turnover and In human tissues, GM2 degradation proceeds mainly with the removal of the terminal N-acetylgalactosamine residue by Hex A with the help of the lipid binding and transfer protein, GM2AP, to form GM3, which is degraded to lactosylceramide by an α-sialidase with the help of Sap B [49].…”

“…A sialidase slowly removes sialic acid from the monosialogangliosides GM1 and GM2, generating the respective asialo-derivatives, GA1 and GA2, which are further catabolized by lysosomal hexosaminidases and β-galactosidases. Therefore, Hex A deficient mice avoid a major glycolipid accumulation and are a poor model of TSD [9,35]. They keep a slow GM2 turnover and generate only a minor GM2 accumulation, especially in Purkinje and Pyramidal cells, allowing an almost normal life span [35].…”

“…2020, 21, 2566 2 of 30 we identified stimulators and inhibitors that strongly affect various catabolic sphingolipid pathways in the lysosome. Primary lysosomal storage compounds like sphingomyelin, cholesterol, and chondroitin sulfate were identified as inhibitors of GSL-catabolism triggering a secondary GSL-accumulation in Niemann-Pick diseases and in MPS [6][7][8][9]. For instance, sphingomyelin is an effective inhibitor of cholesterol secretion from the late endosomal and lysosomal compartment explaining the enormous secondary lysosomal cholesterol accumulation in Niemann-Pick disease types A and B [10].…”

Whole cell response to receptor stimulation involves many deep and distributed subcellular processes

“…CTP is a co-factor for neuronal phosphatidylethanolamine and -choline synthesis via the Kennedy pathway (Vincenzetti et al 2016) and uridine induces intracellular CTP increase and neurite outgrowth (Pooler et al 2005). UTP and CTP are co-factors for ganglioside synthesis (Sandhoff and Sandhoff 2018). Though pyrimidine de novo synthesis was also up-regulated, we could only document the dependence of NOG on pyrimidine salvage (Tymp), but not on pyrimidine de-novo synthesis (Cad knock down showed no effect, Dhodh knock down increased NOG) ( Figure 2B, Suppl.…”