Metabolic and cellular bases of sphingolipidoses.

Lysosomes are cellular stomachs. They degrade macromolecules and release their components as nutrients into the cytosol. Digestion of sphingolipids and other membrane lipids occurs at luminal intraendosomal vesicles and IMs (intraendosomal membranes). Sphingolipid and membrane digestion needs catabolic hydrolases with the help of lipid-binding proteins [SAPs (sphingolipid activator proteins)] and anionic lipids such as BMP [bis(monoacylglycero)phosphate]. Inherited defects of hydrolases or SAPs or uptake of cationic amphiphilic drugs cause lipid accumulation, eventually leading to death, especially in inherited sphingolipid storage diseases. IMs are formed during endocytosis and their lipid composition is adjusted for degradation. Their cholesterol content, which stabilizes membranes, decreases and the level of negatively charged BMP, which stimulates sphingolipid degradation, increases. At the level of late endosomes, cholesterol is transported out of the luminal vesicles preferentially by cholesterol-binding proteins, NPC (Niemann-Pick type C)-2 and NPC-1. Their defects lead to an endolysosomal accumulation of cholesterol and sphingolipids in Niemann-Pick type C disease. BMP and ceramide stimulate NPC-2-mediated cholesterol transfer, whereas sphingomyelin inhibits it. Anionic membrane lipids also activate sphingomyelin degradation by ASM (acid sphingomyelinase), facilitating cholesterol export by NPC-2. ASM is a non-specific phospholipase C and degrades more than 23 phospholipids. SAPs are membrane-perturbing proteins which solubilize lipids, facilitating glycolipid digestion by presenting them to soluble catabolic enzymes at acidic pH. High BMP and low cholesterol levels favour lipid extraction and membrane disintegration by saposin A and B. The simultaneous inherited defect of saposins A-D causes a severe membrane and sphingolipid storage disease, also disrupting the water permeability barrier of the skin.