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Roles of Sialic Acid Diversity in Mammalian Brain Evolution /

  • Author(s): Davies, Leela Rhian Lobo
  • et al.
Abstract

The sialic acids N-acetylneuraminic acid (Neu5Ac) and N- glycolylneuraminic acid (Neu5Gc) are commonly found in the glycolipids and glycoproteins that cover all vertebrate cell surfaces. The brain, which has a higher concentration of sialic acids than any other tissue, exhibits some interesting features of sialic acid biology with evolutionary implications. In the brain of all vertebrate species tested to date, Neu5Ac is present at high quantities, whereas Neu5Gc is very low or even absent. This conserved exclusion suggests a selective pressure against Neu5Gc expression in the vertebrate brain. We have hypothesized that the mechanism for this pressure may be that Neu5Gc presence inhibits the appropriate enzymatic degradation of polysialic acid (polySia), a polymer of alpha2-8 linked sialic acid. PolySia is primarily found in brain tissue, and has been implicated in a wide array of important developmental processes including migration, neurite outgrowth, plasticity, and repair. In Chapter 3, we test the viability of this hypothesis in vitro. We demonstrate that Neu5Gc present in polySia does in fact exhibit a relative resistance to degradation by vertebrate and bacterial sialidases. To determine whether this process is meaningful in vivo, and to further understand the presumed detrimental effects of Neu5Gc on the vertebrate brain, we have developed transgenic mouse models that overexpress Neu5Gc in brain tissue. In Chapter 4, we describe these ongoing efforts. Studies in the near future will determine whether these mice exhibit problems with polySia degradation, and comprehensively characterize their behavioral and anatomical phenotypes. Lastly, in Chapter 5, we explore the potential role of polySia in human brain evolution. We focus on the effects of a single human-specific mutation in one of the biosynthetic enzymes of polySia, ST8Sia-II. Preliminary work suggests that this mutation decreases the stability of the enzyme while increasing the length of its synthesized polySia product. These effects may have implications for the regulation of polySia, and its associated processes, in the human brain. Together, the work discussed here examines potential roles that sialic acid metabolism may have played in mammalian brain evolution

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