title: Physiological Exploration of the Long Term Evolutionary Selection against Expression ofN-Glycolylneuraminic Acid in the Brain.
abstract: All 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 areN-acetylneuraminic acid (Neu5Ac) andN-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-specificCmahtransgenic mice. Such Neu5Gc overexpression in the brain resulted in abnormal locomotor activity, impaired object recognition memory, and abnormal axon myelination. Brain-specificCmahtransgenic 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.
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Naito-Matsui
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Leela R L
authors.initials: LR
authors.lastname: Davies
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.|the Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto 606-8507, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Takematsu
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Hsun-Hua
authors.initials: HH
authors.lastname: Chou
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Pam
authors.initials: P
authors.lastname: Tangvoranuntakul
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine.
authors.forename: Andrea
authors.initials: A
authors.lastname: Verhagen
authors.affiliation: Neuroscience Behavioral Testing Core.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Heyser
authors.affiliation: the Departments of Neurology and.
authors.forename: Seung-Wan
authors.initials: SW
authors.lastname: Yoo
authors.affiliation: Glycobiology Research and Training Center, and.
authors.forename: Biswa
authors.initials: B
authors.lastname: Choudhury
authors.affiliation: the Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide SA 5005, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: the Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide SA 5005, Australia.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California 92093-0687.
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.affiliation: Pharmacology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
authors.affiliation: From the Departments of Medicine and Cellular and Molecular Medicine, a1varki@ucsd.edu.|Glycobiology Research and Training Center, and.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004730:Endothelium, Vascular / Q000378:metabolism; D008124:Locomotion; D013058:Mass Spectrometry; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009438:Neuraminic Acids / Q000378:metabolism*
chemical_list: D009438:Neuraminic Acids; C032592:N-glycolylneuraminic acid
keywords: N-glycolylneuraminic acid; bacterial toxin; behavior; brain; ganglioside; glycobiology; myelin-associated glycoprotein; sialic acid