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Reversal of non‐hydroxy : α‐hydroxy galactosylceramide ratio and unstable myelin in transgenic mice overexpressing UDP‐galactose : ceramide galactosyltransferase
Author(s) -
Fewou Simon N.,
Büssow Heinrich,
SchaerenWiemers Nicole,
Vanier Marie T.,
Macklin Wendy B.,
Gieselmann Volkmar,
Eckhardt Matthias
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03221.x
Subject(s) - galactosyltransferase , ceramide , sphingolipid , genetically modified mouse , myelin , biochemistry , cerebroside , transgene , galactose , chemistry , biology , enzyme , endocrinology , central nervous system , gene , apoptosis
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 α‐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 α‐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 α‐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.