Gangliosidoses are caused by monogenic defects of a specific
hydrolase or an ancillary
sphingolipid activator
protein essential for a specific step in the catabolism of
gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable
gangliosides and
glycosphingolipids. In reality, however, predominantly small
gangliosides also accumulate 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,
saposin A and B), essential for the catabolism of many
gangliosides and
glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal
ganglioside catabolism and
cholesterol turnover. 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 more
lysosomal storage diseases, so far without known molecular basis.