Abstract
BackgroundThe 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.ResultsFa2h-/-/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-/- miceConclusionsThese 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.
Highlights
The sphingolipids galactosylceramide (GalCer) and sulfatide are major myelin components and are thought to play important roles in myelin function
In order to test the hypothesis that hydroxylated fatty acid containing (HFA)-GlcCer partially compensates the loss of HFA-GalCer in Cgt-/mice and thereby prevents a more severe phenotype, we generated Cgt-/- mice with an additional deficiency in GlcCer levels are reduced in CNS and PNS of fatty acid 2-hydroxylase (Fa2h)-/-/Cgt-/mice when compared to Cgt-/- mice thin layer chromatography (TLC) analysis of total brain lipids from wild-type, Fa2h-/, Cgt-/- and Fa2h-/-/ceramide galactosyltransferase-deficient (Cgt-/-)mice showed significant levels of HFA-GlcCer in Cgt-/-mice, in line with earlier reports
Analysis of peripheral nerves revealed a reduction of GlcCer in Fa2h-/-/Cgt-/- mice by about 60% compared to Cgt-/-mice (Figure 3B, D)
Summary
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, are still able to form compact myelin. Galactosylceramide (GalCer) is the most abundant sphingolipid of mammalian myelin [1] It is synthesized in the endoplasmic reticulum by UDP-galactose:ceramide galactosyltransferase (encoded by the Cgt gene). In the absence of a functional Cgt gene, compact myelin can be formed, which is, unstable and Cgt-/- mice develop tremors and ataxia at 3 to 4 weeks of age [3,4] This phenotype could be explained by disturbed axonglial contacts at the paranodes in the CNS caused by mistargeting of essential adhesion molecules, NF-155 and Caspr [5,6]. Myelin appear to be more stable in Gal3st1-deficient mice, suggesting additional, yet less defined roles of GalCer in myelin [8]
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