Reversal of non-hydroxy:alpha-hydroxy galactosylceramide ratio and unstable myelin in transgenic mice overexpressing UDP-galactose:ceramide galactosyltransferase.

Abstract

The sphingolipids galactosylceramide and sulfatide are important for the formation and maintenance of myelin. Transgenic mice overexpressing the galactosylceramide synthesizing enzyme UDP-galactose:ceramide galactosyltransferase in oligodendrocytes display an up to four-fold increase in UDP-galactose:ceramide galactosyltransferase activity, which correlates with an increase in its products monogalactosyl diglyceride and non-hydroxy fatty acid-containing galactosylceramide. Surprisingly, however, we observed a concomitant decrease in alpha-hydroxylated galactosylceramide such that total galactosylceramide in transgenic mice was almost unaltered. These data suggest that UDP-galactose:ceramide galactosyltransferase activity does not limit total galactosylceramide level. Furthermore, the predominance of alpha-hydroxylated galactosylceramide appeared to be determined by the extent to which non-hydroxylated ceramide was galactosylated rather than by the higher affinity of UDP-galactose:ceramide galactosyltransferase for alpha-hydroxy fatty acid ceramide. The protein composition of myelin was unchanged with the exception of significant up-regulation of the myelin and lymphocyte protein. Transgenic mice were able to form myelin, which, however, was apparently unstable and uncompacted. These mice developed a progressive hindlimb paralysis and demyelination in the CNS, demonstrating that tight control of UDP-galactose:ceramide galactosyltransferase expression is essential for myelin maintenance.

• Authors: Simon N Fewou, Heinrich Büssow, Nicole Schaeren-Wiemers, Marie T Vanier, Wendy B Macklin, Volkmar Gieselmann, Matthias Eckhardt
• Journal: Journal of neurochemistry (J Neurochem) Vol. 94 Issue 2 Pg. 469-81 (Jul 2005) ISSN: 0022-3042 [Print] England
• PMID: 15998297 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Galactosylceramides
• Myelin-Associated Glycoprotein
• RNA, Messenger
• Psychosine
• Galactosyltransferases
• Ugt8a protein, mouse
• Ganglioside Galactosyltransferase

Topics

• Age Factors
• Animals
• Behavior, Animal (physiology)
• Blotting, Northern (methods)
• Blotting, Western (methods)
• Brain (anatomy & histology, metabolism)
• Chromatography, Thin Layer (methods)
• Fatty Acids (metabolism)
• Galactosylceramides (metabolism)
• Galactosyltransferases (genetics, metabolism)
• Ganglioside Galactosyltransferase
• Gene Expression Regulation, Developmental (physiology)
• In Situ Hybridization (methods)
• Mice
• Mice, Transgenic
• Microscopy, Electron, Transmission (methods)
• Motor Activity (genetics)
• Myelin Sheath (metabolism)
• Myelin-Associated Glycoprotein (metabolism)
• Optic Nerve (ultrastructure)
• Psychosine (metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Rotarod Performance Test (methods)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization (methods)