Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration

Abstract

Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity, including regeneration. Together, vertebrate brain sialoglycans are key regulatory components that contribute to proper development, maintenance, and health of the nervous system.

Engineering of complex protein sialylation in plants

“…Selective polysialylation determined by specific core residues has been reported for glycoproteins expressed in CHO cells (30). Nevertheless, others have shown that distinct types of glycans are not required for polyST activity (1).…”

“…These negatively charged sugar residues (i.e., N-acetylneuraminic acid) play essential roles in many aspects of life: e.g., in cell-cell interactions, in cell signaling, and for protein stability (1,2). A unique feature of Sia is that, unlike other sugars, it often forms homo-oligomers or polymers, with its most complex form polysialic acid (polySia) reaching a degree of polymerization up to 400 (3).…”

“…This sugar polymer is remarkable in that it plays multiple roles across different species from bacteria to humans. Its exceptional physicochemical properties provide the polySia with a large exclusion volume that physically inhibits interactions mediated by polySia-containing molecules, as shown for the major polySia carrier in humans, the neural cell adhesion molecule, NCAM (1,2,4). Recent studies demonstrated the effect of polySia in a variety of basic biological processes, like neural cell regeneration and antiinflammatory processes (5).…”

“…Advanced technologies to generate and probe diverse sialylated glycoproteins are necessary not only to further elucidate the biological significance of sialic acidcontaining molecules but also to pursue medicinal and industrial applications. For the recombinant expression of sialylated proteins, preferentially mammalian/human cells are used because they are able to cap N-glycans (e.g., β1,4-linked galactose) with α2,3-linked and α2,6-linked Sia, the latter representing the prevalent variant in human cells (1). Although such cells produce properly sialylated glycoproteins, they have several limitations, like glycan heterogeneity and the incapability to produce distinct glycoforms on demand, that hamper further investigation on the biological impact of sialylation and the development of optimized therapeutic proteins.…”

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

“…Experiments in mice have shown that the interaction of myelin-associated glycoprotein (MAG) with gangliosides on the axon surface is essential for the stability of axonmyelin units (Schnaar, 2010;Schnaar et al, 2014). MAG is a sialic-acid-binding lectin (Siglec-4) with high specificity for N-acetylneuraminic acid (Neu5Ac) (Collins et al, 1997).…”