Description:
<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Background</jats:title>
<jats:p>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 (<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup>) 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 <jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice with an additional deletion of the fatty acid 2-hydroxylase (<jats:italic>Fa2h</jats:italic>) gene.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>
<jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/Cgt<jats:sup>-/-</jats:sup> double-deficient mice lack sulfatide, GalCer, and in addition HFA-GlcCer and sphingomyelin. Interestingly, compared to <jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice the amount of GlcCer in CNS myelin was strongly reduced in <jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice by more than 80%. This was accompanied by a significant increase in sphingomyelin, which was the predominant sphingolipid in <jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice. Despite these significant changes in myelin sphingolipids, compact myelin was formed in <jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice, and g-ratios of myelinated axons in the spinal cord of 4-week-old <jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice did not differ significantly from that of <jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice, and there was no obvious phenotypic difference between <jats:italic>Fa2h</jats:italic>
<jats:sup>-/-</jats:sup>/<jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> and <jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>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 <jats:italic>Cgt</jats:italic>
<jats:sup>-/-</jats:sup> mice does not functionally compensate the loss of HFA-GalCer.</jats:p>
</jats:sec>