Abstract
The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. GM2 is also a secondary storage compound in lysosomal storage diseases such as Niemann-Pick disease types A-C, with primary storage of SM in type A and cholesterol in types B and C, respectively. The reconstitution of GM2 catabolism at liposomal surfaces carrying GM2 revealed that incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by β-hexosaminidase A assisted by GM2 activator protein, while anionic lipids, ceramide, fatty acids, lysophosphatidylcholine, and diacylglycerol stimulate GM2 catabolism. In contrast, the hydrolysis of the synthetic, water-soluble substrate 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-d-glucopyranoside was neither significantly affected by membrane lipids such as ceramide or SM nor stimulated by anionic lipids such as bis(monoacylglycero)phosphate added as liposomes, detergent micelles, or lipid aggregates. Moreover, hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein, while the stimulating lipids enhanced lipid mobilization.
Highlights
The catabolism of ganglioside GM2 is dependent on three gene products
The lipid binding and transfer protein GM2 activator protein (GM2AP) is known to play an essential role in the catabolism of GM2 by hexosaminidase A (Hex A) at the intralysosomal luminal vesicle (ILV) [15]
We used a lipid mobilization assay to analyze the g-rGM2AP-mediated solubilization of membrane lipids and their degradation products occurring in the lysosomes, such as SM, Chol, DAG, Cer, lyso-PC, free fatty acids, So, and Sa
Summary
The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. Membrane lipids and their degradation compounds control GM2 catabolism at intralysosomal luminal vesicles. Proper catabolism of sphingolipids with short oligosaccharide head groups requires special lipid binding and transfer proteins, so-called sphingolipid activator proteins, that mediate the interaction of the membrane-bound lipid substrate and the water-soluble enzyme [13,14,15,16]. They consist of the saposins A–D and the GM2 activator protein (GM2AP).
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