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Recent advances in glycobiology have revealed the importance of sugar chains as biosignals for multi-cellular organisms including cell-cell communication, quality control of proteins, and sorting of proteins within cells. Unlike proteins and nucleic acids, which are linear molecules, sugar chains are branched. Furthermore, the number of positional isomers and anomeric configurations, i.e., those not shared by nucleic acids and proteins, can form many structures with a small number of units. Such complexity made their precise analysis difficult and their functional aspects obscure for a long time. However, newly developed and sensitive methods to elucidate the structures of the sugar chains have enabled the precise determination of increasingly smaller amounts of sugar chains. This is especially beneficial for structurally unusual and new sugar chains that are difficult to isolate from limited sources of tissues. Sugar chain-bearing glycoproteins, glycolipids or proteoglycans are found at the cell surface and among extracellular compartments that have been shown play pivotal roles in nervous system development, modifying synaptic activity and regenerating nerve connections after damage in the adult. For example, it has been shown that polysialic acid chains are attached to the embryonic form of the neural cell adhesion molecules (NCAMs) and their chain lengths dramatically decreased in the adult form of NCAM. On the other hand, in adult brain, the polysialylated NCAM is present in the hippocampus where ongoing neurogenesis, cell migration, axon outgrowth and synaptic plasticity are observed. The polysialic acid on NCAM is regarded as an important regulator that prevents strong binding between NCAMs.
The biosynthesis of sugar chains is not formed by the intervention of a template but is under the control of the expression of glycosyltransferases, their substrate specificity, and their localization in specific tissues including the nervous system. There is growing evidence that these enzymes play a variety of roles in cellular differentiation and development, as well as in disease processes. The removal of a specific glycosyltransferase gene in knockout mice indicates that some glycosyltransferases are essential for neuronal development, and their defects lead to neurological abnormalities (1). The importance of sugar chains for the nervous system is further highlighted by congenital disorders of glycosylation (caused by defects in N-linked sugar chains) that result in hypotonia, psychomotor retardation and other neuropathological symptoms. Further, recent data strengthen also the importance of sugar chains not part of the N-linked pathway in the nervous system because aberrant O-mannosylation is the primary cause of some forms of congenital muscular dystrophy and neuronal migration disorder (2).
An understanding of the functional roles of sugar chains in the nervous system will undoubtedly expand our knowledge on nervous system function, and sugar chains might become new targets for the treatment of pathological conditions of the nervous system. Although there are difficulties in elucidating the complex structure-function relationships of sugar chains, glyco-neurobiology will come of age in cellular and molecular medicine of the nervous system. In this series each article will summarize the present state of knowledge on sugar chains as mediators of cell recognition in the nervous system.
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| References |
(1) |
Lowe JB, Marth JD: A genetic approach to Mammalian glycan function. Annu. Rev. Biochem., 72, 643-691, 2003 |
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(2) |
Endo T, Toda T: Glycosylation in congenital muscular dystrophies. Biol. Pharm. Bull., 26, 1641-1647, 2003 |
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