IN-VITRO ACCUMULATION OF GLUCOCEREBROSIDE IN NEUROBLASTOMA-CELLS - A MODEL FOR STUDY OF GAUCHER DISEASE PATHOBIOLOGY

Gaucher disease is the most common lysosomal glycosphingolipid storage disease; decreased activity of glucosylceramide beta-glucosidase (GCa se) results in the accumulation of glucocerebroside (GlcCer) in macrop hage-derived cells, The most devastating types of Gaucher disease also involve neuronopathology, thought to be mediated by intracellular Glc Cer accumulation in the brain, In this study, we developed an in vitro neuronal cell model for accumulation of endogenous GlcCer to enable s tudies on the cellular basis for the neuronopathology of this disease. A human neuroblastoma cell line (SH-SY5Y) was selected because it pro duced appreciable GCase, When these cells were treated with conduritol B epoxide (CBE), a competitive, irreversible inhibitor of this enzyme , GCase levels fell precipitously, while other lysosomal hydrolase lev els were unaffected. Relative to untreated control cells, the CBE-trea ted cells accumulated higher levels of GlcCer, but not other related g lycolipids, over time. Thus, this in vitro system displayed many essen tial biological parameters relevant for studies on cellular events res ponsible for the neurologic damage that occurs in some types of Gauche r disease, This model should also be useful in investigations of the n ormal role of sphingolipids in neuronal cell function. (C) 1996 Wiley- Liss, Inc.