Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes. Genetically determined deficiencies in their catabolic pathways cause the excessive intralysosomal accumulation of these lipids and give rise to a group of inherited metabolic diseases, the sphingolipidoses. The progression of these disorders often involves severe degeneration of the nervous system, and for nearly all of them, no effective treatment is available to date. Here, we discuss the physiological functions of glycosphingolipids and the topology and mechanism of their metabolism. The molecular defects associated with these storage disorders as well as their pathophysiological consequences and potential therapeutic prospects are presented. Finally, the importance of recently available animal models for the investigation of pathogenesis and the evaluation of future therapy approaches is discussed.
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