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 ( Fig. 1 ) ( 3-5 ).Ceramide consists of a fatty acid acyl chain that var-Abstract Glycosphingolipids (GSLs) and gangliosides are a group of bioactive glycolipids that include cerebrosides, globosides, and gangliosides.These lipids play major roles in signal transduction, cell adhesion, modulating growth factor/hormone receptor, antigen recognition, and protein traffi cking.Specifi c genetic defects in lysosomal hydrolases disrupt normal GSL and ganglioside metabolism leading to their excess accumulation in cellular compartments, particularly in the lysosome, i.e., lysosomal storage diseases (LSDs).The storage diseases of GSLs and gangliosides affect all organ systems, but the central nervous system (CNS) is primarily involved in many.Current treatments can attenuate the visceral disease, but the management of CNS involvement remains an unmet medical need.Early interventions that alter the CNS disease have shown promise in delaying neurologic involvement in several CNS LSDs.Consequently, effective treatment for such devastating inherited diseases requires an understanding of the early developmental and pathological mechanisms of GSL and ganglioside fl ux (synthesis and degradation) that underlie the CNS diseases.These are the focus of this review.-