Neuropathology and Applied Neurobiology (2002), 28, 343–357 © 2002 Blackwell Publishing Ltd 343 Blackwell Science, LtdOxford, UK NANNeuropathology and Applied Neurobiology0305-1846Blackwell Science Ltd, 2002 28 422 Glycosphingolipid lysosomal storage diseases M. Jeyakumar et al. 10.1046/j.0305-1846.2002.00422.x Review Article343357BEES SGML Review Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis M. Jeyakumar, T. D. Butters, R. A. Dwek and F. M. Platt Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK M. Jeyakumar, T. D. Butters, R. A. Dwek and F. M. Platt (2002) Neuropathology and Applied Neurobiology 28, 343–357 Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabo- lism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders fre- quently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incom- plete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies. Keywords: Lysosomal storage disease, pathogenesis, glycosphingolipid biosynthesis inhibitors, substrate reduction therapy, gangliosides Correspondence: Fran Platt, Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Introduction Glycosphingolipids (GSLs) are found in the membranes of all eukaryotic cells but have increased in complexity over evolutionary time. Many functions have been ascribed to GSLs, although in general our knowledge of their in vivo roles remains incomplete [42]. They are thought to func- tion primarily at the cell surface and participate in mem- brane microdomains/rafts essential for the signalling of certain proteins, including those with GPI (glycosylphos- phatidylinositol) anchors [23]. Most GSLs have a com- mon core structure that is composed of the hydrophobic lipid ceramide linked to either glucose or galactose [31,80]. The ceramide moiety is embedded in the outer leaflet of the plasma membrane and the carbohydrate por- tion is exposed on the cell surface. GSLs derived from gluc- osylceramide (GlcCer) are found throughout the body whereas those derived from galactosylceramide (GalCer, and its sulphated derivative sulphatide) play a specialized role within the central nervous system (CNS) and contrib- ute to the formation and stability of myelin [10]. GalCer- based GSLs are also expressed by cells of the kidney at lower levels than brain but at higher levels than other tis- sues. This review focuses on GlcCer-based GSLs. GSL biosynthesis and catabolism GSLs are synthesized within the Golgi apparatus by the sequential addition of monosaccharides to ceramide [31]. Two main families of GSLs result: the neutral GSLs and the gangliosides. The gangliosides contain one or more sialic acid residues; they are found throughout the tissues of mammals but are particularly abundant on the surface of cells of the CNS [42]. We currently have a relatively poor understanding of their roles in both the developing and the adult CNS. A summary of GSL biosynthesis is shown in Figure 1. GSLs typically recycle via the Golgi apparatus [71] as part of normal turnover, GSLs are routed to the lysosome where they are degraded by the sequential action of spe- cific glycohydrolases. These enzymes trim the GSL by one