Cascades of Catabolic Errors generate complex Pathologies in LSDs
Sphingolipidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of sphingolipids. Inherited defects of a promiscuous hydrolase or an unspecific lipid binding protein cause a primary accumulation of multiple undegradable sphingolipids and glycosphingolipids. However, predominantly small gangliosides and glycolipids accumulate also in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposins A and B), which are essential for the catabolism of many gangliosides and sphingolipids. They are also inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol release from the late endosomal compartment. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many other lysosomal storage diseases, so far without known molecular basis.