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

Abstract

Edited by Amanda J. FosangAll vertebrate cell surfaces display a dense glycan layer often terminated with sialic acids, which have multiple functions due to their location and diverse modifications. The major sialic acids in most mammalian tissues are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), the latter being derived from Neu5Ac via addition of one oxygen atom at the sugar nucleotide level by CMP-Neu5Ac hydroxylase (Cmah). Contrasting with other organs that express various ratios of Neu5Ac and Neu5Gc depending on the variable expression of Cmah, Neu5Gc expression in the brain is extremely low in all vertebrates studied to date, suggesting that neural expression is detrimental to animals. However, physiological exploration of the reasons for this long term evolutionary selection has been lacking. To explore the consequences of forced expression of Neu5Gc in the brain, we have established brain-specific Cmah transgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specific Cmah transgenic mice were also lethally sensitive to a Neu5Gc-preferring bacterial toxin, even though Neu5Gc was overexpressed only in the brain and other organs maintained endogenous Neu5Gc expression, as in wild-type mice. Therefore, the unusually strict evolutionary suppression of Neu5Gc expression in the vertebrate brain may be explained by evasion of negative effects on neural functions and by selection against pathogens.

Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

“… Terabayashi et al (1992) analyzed brain gangliosides of ten cetacean species, reporting the presence of low levels of Neu5Gc in only three species: sperm whale, Dall’s porpoise, and killer whale. These results are in contrast with the fact that vertebrates generally do not express Neu5Gc in the brain, where it is believed to have adverse effects ( Naito-Matsui et al 2017 ). In addition, these species are carnivorous, thus raising the possibility that the observed Neu5Gc might have a dietary origin.…”

“…Previous studies did not detect Neu5Gc in the liver of the frog Rana esculata ( Schauer et al 1980 ) or in the brain gangliosides of X. laevis ( Rizzo et al 2002 ). It should be noted, nonetheless, that Neu5Gc is usually not detected in vertebrate brain, where it appears to have adverse effects ( Naito-Matsui et al 2017 ). The red blood cells of the salamander Amphiuma means also have been reported to contain only Neu5Ac ( Pape et al 1975 ).…”

Vertebrate Alpha2,8-Sialyltransferases (ST8Sia): A Teleost Perspective

“…Whereas in mammals, homopolymers of Neu5Ac residues are typically formed [61], in rainbow trout eggs, polymers can consist of Neu5Ac, Neu5Gc, and KDN in addition to their O-acetylated forms [62]. One explanation could be a better accessibility to different sialic acids in fish, because, in transgenic mice-showing a Neu5Gc overexpression in brain-besides Neu5Ac, Neu5Gc also seems to be utilized to build polySia [63].…”

Invisible Designers: Brain Evolution Through the Lens of Parasite Manipulation

“…The ability to synthesize Neu5Gc has been lost independently by humans, several other mammals, birds, and platypuses (Springer and Gagneux 2013;Gagneux et al 2017); but even vertebrates that express high levels of Neu5Gc in bodily tissues show extremely low amounts of this molecule in the brain. There is recent evidence that suppression of Neu5Gc protects the brain from bacterial toxins that use it as a binding site (Naito-Matsui et al 2017). To my knowl-edge, the potential implications of parasitedriven glycan evolution for brain physiology and function have yet to be explored.…”