A historical perspective of the glycosphingolipids and sphingolipidoses

Abstract

Glycosphingolipids are a polysaccharide chain between 1 and 40 carbohydrate residues long glycosidically linked to ceramide (a long-chain aliphatic amino-alcohol or sphingoid) that is embedded in the cell plasma membrane with the carbohydrate moiety on the outside. The sphingoid imparts rigidity to the membrane and the carbohydrate tails protect the cell surface and have functions in relation to cell adhesion, growth, regulation, differentiation, cell interaction, recognition and signalling. They provide adhesion sites for pathogens and change during oncogenic transformation. Ceramide is also a component of sphingomyelin. Glycosphingolipids are degraded by lysosomal hydrolysis. The sphingolipidoses are a series of diseases in which mutations affecting the enzymes catalysing the last 11 steps of this process causing abnormal compounds proximal to the metabolic block to accumulate intralysosomally. Thus, they are a sub-group of the lysosomal storage diseases. The degradation of sphingolipids containing three or less carbohydrate residues requires a sphingolipid activator protein and mutations affecting these proteins also cause abnormal glycosphingolipid storage.With one exception (Fabry disease, which is X linked) the sphingolipidoses are inherited autosomally. The phenotypic manifestations of the individual sphingolipidoses are variable although the more severe variants are usually the better known. They have generally been regarded as untreatable but notable therapeutic advances are being made by enzyme replacement therapy and regulating the rate of glycosphingolipid synthesis by inhibiting UDP-glucose-N-acylsphingosine d-glucosyl transferase (CerGlcT), which is the first reaction on the pathway of glycosphingolipid synthesis. The compounds used are N-alkylated iminosugars whose glucose and galactose stereochemistries inhibit CerGlcT.Prenatal and carrier state diagnosis, genetic counselling and the abortion of affected foetuses are reducing the incidence of some of the most severe sphingolipidoses in certain high-incidence populations.

Structures of the human ceramide activator protein saposin D

“…Sphingolipids (SLs) are essential components of eukaryotic cell membranes, with roles in cell adhesion, cell growth, cell regulation, intracellular trafficking and interactions with signal molecules and toxins (Sandhoff & Kolter, 2003;Watts, 2003). Typically, two proteins are involved in the lysosomal breakdown of an SL: an acid hydrolase and an activator protein.…”

Α-Glucosidase Deficiency Promotes Increasing Protein Oxidative Damage in Pompe Disease Patients

“…The enzyme deficiency of lysosomal hydrolases, which are enzymes that act on degradation in lysosomes, causes various genetic diseases, classified as lysosomal storage diseases (LSDs). These diseases are severe, with a broad spectrum of skeletal abnormalities, impaired nervous system, organ dysfunction and accumulation of lipids in complex tissues [3].…”