The Chemical Neurobiology of Carbohydrates

Abstract

The cell surface displays a complex array of oligosaccharides, glycoproteins, and glycolipids. This diverse mixture of glycans contains a wealth of information, modulating a wide range of processes such as cell migration, proliferation, transcriptional regulation, and differentiation. Glycosylation is one of the most ubiquitous forms of post-translational modification, with more than 50% of the human proteome estimated to be glycosylated. Glycosylation adds another dimension to the complexity of cellular signaling and expands the ability of a cell to modulate protein function. The structural complexity of glycan modifications ranges from the addition of a single monosaccharide unit to polysaccharides containing hundreds of sugars in branched or linear arrays. This chemical diversity enables glycans to impart a vast array of functions, from structural stability and proteolytic protection to protein recognition and modulation of cell signaling networks. Emerging evidence suggests a pivotal role for glycans in regulating nervous system development and function. For instance, glycosylation influences various neuronal processes, such as neurite outgrowth and morphology, and may contribute to the molecular events that underlie learning and memory. Glycosylation is an efficient modulator of cell signaling and has been implicated in memory consolidation pathways. Genetic ablation of glycosylation enzymes often leads to developmental defects and can influence various organismal behaviors such as stress and cognition. Thus, the complexity of glycan functions help to orchestrate proper neuronal development during embryogenesis, as well as influence behaviors in the adult organism. The importance of glycosylation is further highlighted by defects in glycan structures that often lead to human disease, as exhibited by congenital disorders of glycosylation (CDG).25–29 These are usually inherited disorders resulting from defects in glycan biosynthesis, which are accompanied by severe developmental abnormalities, mental retardation, and difficulties with motor coordination. Such disorders highlight the importance of glycan biosynthesis in human health and development. Because therapeutic treatments are currently limited, investigations into the structure–activity relationships of glycans, as well as disease-associated alterations to glycan structure, are crucial for developing strategies to combat these diseases. Understanding the structure–function relationships of glycans has been hampered by a lack of tools and methods to facilitate their analysis. In contrast to nucleic acids and proteins, oligosaccharides often have branched structures, and their biosynthesis is not template-encoded. As such, the composition and sequence of oligosaccharides cannot be easily predicted, and genetic manipulations are considerably less straightforward. Analytical techniques for investigating oligosaccharide composition, sequence, and tertiary structure are still undergoing development and are far from routine, unlike methods for DNA and protein analysis. Lastly, glycan structures are not under direct genetic control and, thus, are often heterogeneous. This heterogeneity complicates structure–function analyses by traditional biochemical approaches that rely on the isolation and purification of glycans from natural sources. The problems associated with oligosaccharide analysis have hindered efforts to understand the biology of oligosaccharides yet have given chemists a unique opportunity to develop new methods to overcome these challenges. The development of chemical tools for the analysis of glycan structure and function is essential to advance our understanding of the roles of glycoconjugates in regulating diverse biological processes. In this review, we will highlight the emerging area of glyconeurobiology with an emphasis on current chemical approaches for elucidating the biological functions of glycans in the nervous system.

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