Interruption of Ganglioside Synthesis Produces Central Nervous System Degeneration and Altered Axon-Glial Interactions

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 gang...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 8; pp. 2725 - 2730
Main Authors:	Yamashita, Tadashi, Wu, Yun-Ping, Sandhoff, Roger, Werth, Norbert, Mizukami, Hiroki, Ellis, Jessica M., Dupree, Jeffrey L., Geyer, Rudolf, Sandhoff, Konrad, Proia, Richard L., Brady, Roscoe O.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 22-02-2005 National Acad Sciences
Subjects:	Animals Axons Axons - ultrastructure Biochemistry Biological Sciences Brain Brain - pathology Brain - ultrastructure Brain Chemistry Cell Communication Central nervous system Ceramides Gangliosides Gangliosides - biosynthesis Glycosphingolipids Lactosylceramides Lipids Lipids - analysis Mice Mice, Inbred C57BL Mice, Knockout Mutation N-Acetylgalactosaminyltransferases - genetics N-Acetylgalactosaminyltransferases - physiology Nerve Degeneration - metabolism Nerve Degeneration - pathology Nervous system Neuroglia - ultrastructure Neurological disorders Sialyltransferases - genetics Sialyltransferases - physiology White matter
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Summary:	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 neuro-degenerative 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 This paper was submitted directly (Track II) to the PNAS office. T.Y., Y.-P.W., and R.S. contributed equally to this work. To whom correspondence may be sent at the present address: Department of Cell Processing, Institute of Medical Science, Shirokanedai 4-6-1, Minato-ku Tokyo, 108-8639 Japan. E-mail: ty10104@ims.u-tokyo.ac.jp. ††To whom correspondence may be addressed. E-mail: proia@nih.gov. Edited by Roscoe O. Brady, National Institutes of Health, Bethesda, MD, and approved January 14, 2005 Abbreviations: GFAP, glial fibrillary acidic protein; MAG, myelin-associated glycoprotein.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0407785102