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Drastically Abnormal Gluco- and Galactosylceramide Composition Does Not Affect Ganglioside Metabolism in the Brain of Mice Deficient in Galactosylceramide Synthase
Authors:Suzuki  Kunihiko  Vanier  Marie T  Coetzee  Timothy  Popko  Brian
Institution:(1) Neuroscience Center, USA;(2) Departments of Neurology and Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, 27599;(3) Department of Biochemistry and Biophysics, Program in Molecular Biology & Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599;(4) INSERM-CNRS U189, Lyon-Sud School of Medicine and Fondation Gillet-Mérieux, Lyon-Sud Hospital, F-69921 Oullins Cedex, France;(5) Neuroscience Center, CB#7250, University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7250
Abstract:Mice that are genetically deficient in UDP-galactose: ceramide galactosyltransferase are unable to synthesize galactosylceramide. Consequently, sulfatide, which can be synthesized only by sulfation of galactosylceramide, is also totally absent in affected mouse brain. agr-Hydroxy fatty acid-containing glucosylceramide partially replaces the missing galactosylceramide. A substantial proportion of sphingomyelin, which normally contains only non-hydroxy fatty acids, also contains agr-hydroxy fatty acids. These findings indicate that agr-hydroxy fatty acid-containing ceramide normally present only in galactosylceramide and sulfatide is diverted to other compounds because they cannot be synthesized into galactosylceramide due to the lack of the galactosyltransferase. We have examined brain gangliosides in order to determine if agr-hydroxy fatty acid-containing glucosylceramide present in an abnormally high concentration is also incorporated into gangliosides. The brain ganglioside composition, however, is entirely normal in both the total amount and molecular distribution in these mice. One feasible explanation is that UDP-galactose: glucosylceramide galactosyltransferase does not recognize agr-hydroxy fatty acid-containing glucosylceramide as acceptor. This analytical finding is consistent with the relative sparing of gray matter in the affected mice and provides an insight into sphingolipid metabolism in the mouse brain.
Keywords:UDP-galactose: ceramide galactosyltransferase  knockout mouse  galactosylceramide  sulfatide  ganglioside  myelin  animal model
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