Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Abstract

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.

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

“…The B1 variant of TSD shows deficiency in the association of the α and β subunits. The HEXA enzyme subunits have altered specificity where they are defective in GM2 degradation but still act on neutral GSLs, such as GA2 [110].…”

“…GM2 gangliosidosis is a family of LSDs, which manifest due to deficient levels of β-hexosaminidase A resulting in failure to cleave the GalNAcβ residue from GM2, GD2, GT2 and Gb4 ( Figure 1 C,E) and the GlcNAcβ- residues from other GSLs. The variants of the GM2 gangliosidosis LSD family include TSD variants, SD and deficiency of the GM2 activator protein in AB variants [ 110 ], each characterized by mutations to one of the genes involved in GM2 catabolism. The ratio of accumulating gangliosides differs among patients, however, GM2 is the primary storage substrate found in neuronal lysosomes [ 111 ].…”

Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism

“…Animal models and studies in humans demonstrated that impaired GAG degradation causes a deep alteration of cellular homeostasis involving pathways unrelated to the GAG metabolism [10,11,[13][14][15][16]. Indeed, defects in the lysosomal degradation of GAGs can be associated with dysfunctions in several biochemical and physiological processes such as the abnormal composition of membranes with an impact on vesicle fusion and trafficking, altered ganglioside and cholesterol metabolism, proteinase deregulation, impairment of autophagy and mitochondrial functions, and others [14][15][16][17][18][19][20]. Thus, a more detailed understanding of the pathogenetic events downstream of the altered GAG metabolism is still required.…”

Editorial for Special Issue “Gangliosides: Modes of Action and Cell Fates”

“…In particular, the discovery of a representative accumulative disease of GSLs in lysosomes based on the deficiency of their degradation enzymes, Tay-Sach’s disease, by Klenk has made us recognize the presence and significance of glycosphingolipids in our bodies [ 1 ]. However, major issues which researchers face have been pathological effects of accumulated GSLs in CNS and also in all over bodies [ 2 , 3 ]. On the other hand, the characterization of chemical structures of newly-defined GSLs and the biological meaning of individual species of GSLs have been investigated by Yamakawa and Nagai [ 4 ], Wiegandt [ 2 ], Tettamanti [ 5 ], Hakomori [ 6 ], and many other researchers.…”

“…For the basis of the synthesis and degradation of gangliosides, three intriguing papers were published, i.e., ganglioside synthesis by plasma membrane-associated sialyltransferase [ 17 ], dietary control of ganglioside expression in mammalian tissues [ 18 ], and secondary gangliosides and lipid accumulation in lysosomal disease [ 3 ]. Although the majority of glycosyltransferases are considered to localize in Golgi, Vilcaes et al showed that a sialyltransferase exists in the plasma membrane of macrophages.…”