Gangliosides in the Nervous System: Biosynthesis and Degradation

Abstract

Gangliosides, abundant in the nervous system, areknown to play crucial modulatory roles in cellular recognition,interaction, adhesion, and signal transduction, particularly duringearly developmental stages. The expression of gangliosides in thenervous system is developmentally regulated and is closely related tothe differentiation state of the cell. Ganglioside biosynthesis occursin intracellular organelles, from which gangliosides are transportedto the plasma membrane. During brain development, the gangliosidecomposition of the nervous system undergoes remarkable changes and isstrictly regulated by the activities of glycosyltransferases, whichcan occur at different levels of control, includingglycosyltransferase gene transcription and posttranslationalmodification. Genes for glycosyltransferase involved in gangliosidebiosynthesis have been cloned and classified into families ofglycosyltransferases based on their amino acid sequence similarities.The donor and acceptor substrate specificities are determined byenzymatic analysis of the glycosyltransferase gene products. Cell-typespecific regulation of these genes has also been studied. Gangliosidesare degraded by lysosomal exoglycosidases. The action of these enzymesoccurs frequently in cooperation with activator proteins. Severalhuman diseases are caused by defects of degradative enzymes, resultingin massive accumulation of certain glycolipids, including gangliosidesin the lysosomal compartment and other organelles in the brain andvisceral organs. Some of the representative lysosomal storage diseases(LSDs) caused by the accumulation of lipids in late endosomes andlysosomes will be discussed.