Reversal of non-hydroxy:alpha-hydroxy galactosylceramide ratio and unstable myelin in transgenic mice overexpressing UDP-galactose:ceramide galactosyltransferase.
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.
Institut für Physiologische Chemie, University of Bonn, Germany.
Simon N
SN
Fewou
Heinrich
H
Büssow
Nicole
N
Schaeren-Wiemers
Marie T
MT
Vanier
Wendy B
WB
Macklin
Volkmar
V
Gieselmann
Matthias
M
Eckhardt
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002855:Chromatography, Thin Layer / Q000379:methods; D005227:Fatty Acids / Q000378:metabolism; D005699:Galactosylceramides / Q000378:metabolism*; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D051147:Ganglioside Galactosyltransferase; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009900:Optic Nerve / Q000648:ultrastructure; D011609:Psychosine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
D005227:Fatty Acids; D005699:Galactosylceramides; D018992:Myelin-Associated Glycoprotein; D012333:RNA, Messenger; D011609:Psychosine; D005700:Galactosyltransferases; C511214:Ugt8a protein, mouse; D051147:Ganglioside Galactosyltransferase