Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain?

Abstract

The sialic acids N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) differ by a single oxygen atom and are widely found at the terminal position of glycans on vertebrate cell surfaces. In animals capable of synthesizing Neu5Gc, most tissues and cell types express both sialic acids, in proportions that vary between species. However, it has long been noted that Neu5Gc is consistently expressed at trace to absent levels in the brains of all vertebrates studied to date. Although several reports have claimed to find low levels of Neu5Gc-containing glycans in neural tissue, no study definitively excludes the possibility of contamination with glycans from non-neural cell types. This distribution of a molecule – prominently but variably expressed in extraneural tissues but very low or absent in the brain – is, to our knowledge, unique. The evolutionarily conserved brain-specific suppression of Neu5Gc may indicate that its presence is toxic to this organ; however, no studies to date have directly addressed this very interesting question. Here we provide a historical background to this issue and discuss potential mechanisms causing the suppression of Neu5Gc expression in brain tissue, as well as mechanisms by which Neu5Gc may exert the presumed toxicity. Finally, we discuss future approaches towards understanding the mechanisms and implications of this unusual finding.

Physiological Exploration of the Long Term Evolutionary Selection against Expression of N-Glycolylneuraminic Acid in the Brain

“…Effect on Susceptibility to Bacterial Toxin-Given the near complete absence of Neu5Gc in the brains of all Cmah-positive vertebrates studied to date (31), it is reasonable to assume that the persistence of this strong suppression in so many lineages is due to some strong evolutionary selection factor(s). Although we found mild neural abnormalities of various kinds in the NCmahTg mice, none of these would seem to be detrimental enough by themselves to account for such strong selection.…”

“…The fact that expression is not at all tightly regulated in other tissues (30,31) makes this observation all the more intriguing. Moreover, cells, including embryonic stem cells or primary cultured neurons, are usually cultured in medium containing fetal bovine serum, a source of Neu5Gc, suggesting that possibly toxic effects of Neu5Gc do not target individual neural cells but rather affect the overall central nervous system.…”

“…Because of the differential regulation of Cmah expression, the ratio of these two major sialic acids varies markedly among different tissues in different animal species except for certain species like humans that have an inactive CMAH gene (CMAHP) and lack endogenous Neu5Gc expression throughout the body. Even in species that express ample Neu5Gc in other tissues, the brain shows extremely low Neu5Gc expression (Ͻ3%) in all vertebrate species tested to date, from fish to chimpanzees (30,31). In other words, the suppression of Neu5Gc expression in the vertebrate brain appears to be universal to all vertebrates studied so far, regardless of highly variable expression in other cell types (30).…”

Database and data analysis application for structural characterization of gangliosides and sulfated glycosphingolipids by negative ion mass spectrometry

“…As evidenced, NeuGc-containing glycans rarely occur in the brain of vertebrates, and are absent in human brain. 47 Altogether, in the analyzed mixture from calf brain, 16 ganglioside structures, 1 sulfatide, and 3 neutral GSL species were identified. …”

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

“…Neu5Ac is the substrate for another prevalent sialic acid, Nglycolylneuraminic acid (Neu5Gc). Interestingly, expression of the Neu5Ac into Neu5Gc-converting enzyme, CMP-Nacetylneuraminic acid hydroxylase (CMAH), is suppressed in the CNS, suggesting that expression of Neu5Gc in the brain and spinal cord is detrimental for homeostasis (Davies and Varki, 2013).…”