The role of glycosphingolipid metabolism in the developing brain

Abstract

Glycosphingolipids (GSLs) are amphipathic lipids ubiquitously expressed in all vertebrate cells and body fluids, but they are especially abundant in the nervous system. The synthesis of GSLs generally is initiated in the endoplasmic reticulum and completed in the Golgi apparatus, followed by transportation to the plasma membrane surface as an integral component. The amount and expression patterns of GSLs change drastically in brains during the embryonic to postnatal stages. Recent studies have revealed that GSLs are highly localized in cell surface microdomains and function as important components that mediate signal transduction and cell adhesion. Also in developing brains, GSLs are suggested to play important roles in nervous system formation. Disturbance of GSL expression and metabolism affects brain function, resulting in a variety of diseases, particularly lysosomal storage diseases. In this review, we describe some aspects of the roles of GSLs, especially of gangliosides, in brain development.

Fig. 1.

Structures and metabolic pathway of gangliosides (9). The nomenclature for gangliosides and related GSLs is based on that of Svennerholm (49). ARSA, arylsulfatase A; β-gal, lysosomal acid β-galatosidase; CST, cerebroside sulfotransferase; GALC, galactosylceramidase; GalCer, galactosylceramide; GalNAcT, GA2/GM2/GD2/GT2 synthase; GalT-I, LacCer synthase; GalT-II, GA1/GM1/GD1b/GT1c synthase; GalT-III, GalCer synthase; GlcT, GlcCer synthase; GM2A, GM2 activator protein; HEX, β-N-acetylhexosaminidase; SAP, saposin; ST-I, GM3 synthase; ST-II, GD3 synthase; ST-III, GT3 synthase; ST-IV, GM1b/GD1a/GT1b/GQ1c synthase; ST-V, GD1c/GT1a/GQ1b/GT3 synthase; ST-VII, GD1a/GT1aα/GQ1bα/GP1cα synthase.

Fig. 2.

Expression of gangliosides and glycosyltransferases in developing mouse brains (9). Dose (A), molecular species (B) of gangliosides, and expression levels of glycosyltransferases (C) change drastically during development.

Fig. 3.

Neurodevelopmental milestones and concurrent changes in GSL expression.