Sphingolipid metabolism. Sphingoid analogs, sphingolipid activator proteins, and the pathology of the cell

Sphingolipid metabolism and function was investigated using sphingoid analogs, cells from human sphingolipidoses patients, and knockout animals. Treatment of primary cultured murine cerebellar cells with the structurally modified sphingosine base cis-4 methylsphingosine resulted in decreased sphingolipid biosynthesis accompanied by significant morphological changes. Plasma-membrane-derived glycosphingolipids (GSLs) destined for digestion are internalized through the endocytic pathway and delivered to lysosomes. There, GSLs are degraded by the action of exohydrolases, which are supported, in the case of GSLs with short oligosaccharide chains, by sphingolipid activator proteins (SAPs or saposins). The inherited deficiency of activators give rise to sphingolipid storage diseases. The analysis of cultured fibroblasts from corresponding patients suggests a new model for the topology of endocytosis and lysosomal digestion. Mice with disrupted genes for activator proteins and for GM2 degrading hexosaminidases turned out to be useful models for human diseases.