Drastically abnormal gluco- and galactosylceramide composition does not affect ganglioside metabolism in the brain of mice deficient in galactosylceramide synthase

Mice that are genetically deficient in UDP-galactose: ceramide galactosyltr ansferase are unable to synthesize galactosylceramide. Consequently, sulfat ide, which can be synthesized only by sulfation of galactosylceramide, is a lso totally absent in affected mouse brain. alpha-Hydroxy fatty acid-contai ning glucosylceramide partially replaces the missing galactosylceramide. A substantial proportion of sphingomyelin, which normally contains only non-h ydroxy fatty acids, also contains a-hydroxy fatty acids. These findings ind icate that alpha-hydroxy fatty acid-containing ceramide normally present on ly in galactosylceramide and sulfatide is diverted to other compounds becau se they cannot be synthesized into galactosylceramide due to the lack of th e galactosyltransferase. We have examined brain gangliosides in order to de termine if alpha-hydroxy fatty acid-containing glucosylceramide present in an abnormally high concentration is also incorporated into gangliosides. Th e brain ganglioside composition, however, is entirely normal in both the to tal amount and molecular distribution in these mice. One feasible explanati on is that UDP-galactose: glucosylceramide galactosyltransferase does not r ecognize alpha-hydroxy fatty acid-containing glucosylceramide as acceptor. This analytical finding is consistent with the relative sparing of gray mat ter in the affected mice and provides an insight into sphingolipid metaboli sm in the mouse brain.