Myelination in the absence of UDP-galactose: ceramide galactosyl-transferase and fatty acid 2-hydroxylase

Background: The sphingolipids galactosylceramide (GalCer) and sulfatide are major myelin components and are thought to play important roles in myelin function. The importance of GalCer and sulfatide has been validated using UDP-galactose: ceramide galactosyltransferase-deficient (Cgt(-/-)) mice, which are impaired in myelin maintenance. These mice, however, are still able to form compact myelin. Loss of GalCer and sulfatide in these mice is accompanied by up-regulation of 2-hydroxylated fatty acid containing (HFA)-glucosylceramide in myelin. This was interpreted as a partial compensation of the loss of HFA-GalCer, which may prevent a more severe myelin phenotype. In order to test this hypothesis, we have generated Cgt(-/-) mice with an additional deletion of the fatty acid 2-hydroxylase (Fa2h) gene. Results: Fa2h(-/-)/Cgt(-/-) double-deficient mice lack sulfatide, GalCer, and in addition HFA-GlcCer and sphingomyelin. Interestingly, compared to Cgt(-/-) mice the amount of GlcCer in CNS myelin was strongly reduced in Fa2h(-/-)/Cgt(-/-) mice by more than 80%. This was accompanied by a significant increase in sphingomyelin, which was the predominant sphingolipid in Fa2h(-/-)/Cgt(-/-) mice. Despite these significant changes in myelin sphingolipids, compact myelin was formed in Fa2h(-/-)/Cgt(-/-) mice, and g-ratios of myelinated axons in the spinal cord of 4-week-old Fa2h(-/-)/Cgt(-/-) mice did not differ significantly from that of Cgt(-/-) mice, and there was no obvious phenotypic difference between Fa2h(-/-)/Cgt(-/-) and Cgt(-/-) mice Conclusions: These data show that compact myelin can be formed with non-hydroxylated sphingomyelin as the predominant sphingolipid and suggest that the presence of HFA-GlcCer and HFA-sphingomyelin in Cgt(-/-) mice does not functionally compensate the loss of HFA-GalCer.