Multi-system disorders of glycosphingolipid and ganglioside metabolism

Abstract

important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl-and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or fl ipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules ( 2, 3 ). GSL metabolic pathwaysGSL biosynthesis begins with condensation of serine and palmitoyl-CoA catalyzed by serine-palmitoyltransferase (SPT) on the cytoplasmic face of the ER, leading to de novo biosynthesis of ceramide, the core of GSLs (

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

“…15 Gangliosides are sialic acid-containing GSLs. 18 GM3 synthase catalyzes the formation of GM3 from lactosylceramide, corresponding to the first step of complex ganglioside synthesis (a-and b-series). Alternative enzymatic modification of lactosylceramide leads to the synthesis of alternative derivatives (o-, globo-and neolacto-series).…”

Transcription factor Bcl11b controls selection of invariant natural killer T-cells by regulating glycolipid presentation in double-positive thymocytes

“…Ctsl gene down-regulation may contribute to the glycolipid loading defect, as observed in the Ctsl knockout mice (42). The accumulation of G M1 and G A1 gangliosides may be a consequence of the reduced expression of the gene encoding Glb1, which is also likely to impair the iNKT selection process, as shown for GM1 gangliosidosis (12). We do not know whether Bcl11b directly or indirectly controls expression of these genes.…”

“…Specific mutations in critical genes implicated in complex lipid processing are often associated with accumulation of unmetabolized substrates (reviewed in ref. 12). To determine whether Bcl11b-deficient thymocytes present alterations in complex lipid degradation, we evaluated the lipid composition of Bcl11b-deficient thymocytes by HPLC and found accumulation of several sphingolipid species, including lactosylceramide (LacCer), galactosylceramide (GalCer), glucosylceramide (GluCer), and sphingomyelin (Fig.…”

“…12). Such diseases include Tay-Sachs, with mutations in β-hexosaminidase A gene; Sandhoff, with mutations in β-hexosaminidase A/B genes; Fabry, with mutations in α-galactosidase gene; and GM1 gangliosidosis, with mutations in β-galactosidase gene (Glb1).…”

“…Mutations in the acid sphingomyelinase gene (Smpd1) are associated with Niemann-Pick disease types A and B, with accumulation of sphingomyelin, gangliosides, and cholesterol (13), whereas mutations in prosaposin gene cause accumulation of multiple sphingolipids (reviewed in ref. 12).…”