title: Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions.
abstract: Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ty10104@ims.u-tokyo.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.forename: Norbert
authors.initials: N
authors.lastname: Werth
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Ellis
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dupree
authors.forename: Rudolf
authors.initials: R
authors.lastname: Geyer
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D001923:Brain Chemistry; D002450:Cell Communication; D005732:Gangliosides / Q000096:biosynthesis*; D008055:Lipids / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009457:Neuroglia / Q000648:ultrastructure*; D012799:Sialyltransferases / Q000235:genetics / Q000502:physiology
chemical_list: D005732:Gangliosides; D008055:Lipids; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D012799:Sialyltransferases; C021343:haematoside synthetase