Metabolic studies of glycosphingolipid accumulation in mucopolysaccharidosis IIID

Severe neurological deficits and mental retardation are frequently associat ed with disrupted ganglioside metabolism in a variety of gangliosidoses and lysosomal storage disorders. Accumulation of glycosphingolipids (GSLs) in the central nervous system (CNS) of humans and animals affected with severa l types of mucopolysaccharidoses (MPS) also correlates with the severity of neurological dysfunction. Mucopolysaccharidosis type IIID (MPS IIID) is ch aracterized by deficiency in lysosomal N-acetylglucosamine B-sulfatase acti vity and the accumulation and excretion of heparan sulfates and N-acetylglu cosamine 6-sulfate. We investigated the metabolism of GSLs in the prenatal, neonatal, and adult MPS IIID caprine brains and an MPS experimental cell c ulture model. The amounts of total glycolipids in prenatal, neonatal, and a dult MPS IIID caprine brains were about a-fold higher than those in control samples. GM3, GD3, and lactosyl ceramide were the principal GSLs which abn ormally accumulated in caprine RIPS IIID brains. These changes may be, in p art, due to the reduction of sialidase and UDP-N-acetylgalactosamine:GM3 N- acetylgalactosaminyltransferase (GaINAc-T) activities in MPS IIID caprine b rain. To further examine the possible mechanism of GSL accumulation in MPS IIID brains, we employed a cell culture model using suramin-treated neurona l cultures of differentiated P19 cells. HPTLC analysis showed elevated GSLs in suramin-treated cells. Metabolic pulse-chase labeling study revealed th at the GSL accumulation in suramin-treated cells may be attributed to both disturbed biosynthesis and significantly slower degradation of GSLs. In add ition, the consistency of observations in the cell culture and caprine mode ls supports the cell culture system as a means of evaluating GSL metabolic perturbations. (C) 2001 Academic Press.