Regulation of sphingolipid and glycosphingolipid metabolism during neuronal growth and development.

Introduction Sphingolipids (SLs) and glycosphingolipids (GSLs) are ubiquitous components of eukaryotic cell membranes [l]. These lipids are synthesized in the endoplasmic reticulum (ER) and Golgi apparatus, but reside mainly in the outer leaflet of the plasma membrane. Significant variation exists in the types and levels of SLs and GSLs between different cells, and even within the same cell at different stages of development, implying that the regulation of SL and GSL synthesis (and degradation) is cell-type-specific and is developmentally regulated. By definition, all SLs and GSLs are composed of a sphingoid long-chain base, to which a fatty acid is attached via an amide bond at the C-2 position (yielding ceramide) and to which a variety of headgroup moieties can be attached at C-1; variation in SL and GSL structure is due to the large number of combinations of fatty acids and headgroups that can be thus attached (Figure 1). Two major classes of headgroup moiety are known. The first is phosphocholine, whose attachment to ceramide yields the phosphosphingolipid sphingomyelin (SM), a major phospholipid of animal cell membranes. Alternatively, sugars (normally glucose or galactose) are attached at the C-1 position, and it is the sequential attachment of additional sugars (both neutral and acidic) that yields the large variety of neutral and acidic GSLs (i.e. the gangliosides) [2,3]. Further variation in SL and GSL structure is a result of differences in the number of carbon units and in substitutions of