Glycosphingolipid degradation and animal models of GM2-gangliosidoses.

Glycosphingolipids form cell type-specific patterns on the surface of eukaryotic cells. Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane-derived glycosphingolipids into the lysosomes as the digesting organelles. The inherited deficiencies of lysosomal hydrolases and of sphingolipid activator proteins both give rise to sphingolipid storage diseases. Recent research has focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins. The GM2-degrading system is a paradigm for activator protein-dependent lysosomal degradation. Three polypeptide chains contribute to the in vivo degradation of ganglioside GM2: the alpha- and beta-chains of the beta-hexosaminidases and the GM2 activator. Mouse models of Tay-Sachs disease (alpha-chain deficiency), Sandhoff disease (beta-chain deficiency) and GM2 activator deficiency have been described. While the phenotypes of these variants of GM2-gangliosidoses are only slightly different in humans, the animal models show drastic differences in severity and course of the diseases. The reason for this is the specificity of sialidase, which is different between mouse and human. A double-knockout mouse lacking beta-hexosaminidases A, B and S shows a phenotype of mucopolysaccharidosis and gangliosidosis. A substrate deprivation approach to therapy is discussed with respect to animal models of the GM2-gangliosidoses.