Glycobiology World Congress

Biography

Biography: Konrad Sandhoff

Abstract

Lysosomal sphingolipid degradation requires the presence of water-soluble hydrolases, SAPs, anionic phospholipids like BMP, and an acidic pH value. Inherited defects of catabolic hydrolases or SAPs cause various sphingolipidoses. SAPs are membrane-perturbing proteins which facilitate glycolipid digestion by presenting insoluble lipid molecules to soluble catabolic enzymes. SAPs (the GM2-activator and saposins A-D) bind to lipid bilayers and mobilize lipids out of them at acidic pH values. As demonstrated by plasmon resonance studies for saposins A and B, low cholesterol levels and increasing concentrations of BMP favour lipid extraction and membrane disintegration. Variant saposins as identified in patients with Krabbe disease and metachromatic leukodystrophy, respectively, are deficient in mobilizing membrane lipids. The inherited absence of all four saposins (A-D) causes a severe membrane and sphingolipid storage disease, also disrupting the water permeability barrier of the skin. Saposins and glucosylceramidase are also involved in the extracellular catabolism of ultralongchain acylglucosylceramides, key components for the generation of the extracellular lipid layers forming the immune and the water permeability barrier in the stratum corneum of the mammalian skin. Their complete functional deficiency causes perinatal fatal diseases of the collodion baby type. Ongoing in vitro studies indicate that PM-stabilizing lipids, i.e. SM and cholesterol, inhibit several steps of lysosomal SL and glycosphingolipid catabolism, and also lipid solubilisation as studied by Surface Plasmon Resonance and intervesicular (glyco-) lipid transfer activities of several SAPs and NPC2, even in the presence of activating anionic PLs.