Sphingolipid metabolic disorders in Trembler mouse peripheral nerves in vivo result from an abnormal substrate supply

Sphingolipid metabolic pathways in the peripheral nerves of dysmyelinating Trembler mice were studied in vivo, using intraneurally injected [3H]palmitate as the exogenous substrate. The kinetic analysis of the experimental data obtained for the mutant revealed that, as in normal nerves, two metabolically and kinetically independent pathways are implicated in the biosynthesis of the major peripheral nerve sphingolipids: the ceramide pathway and another pathway in which there is no detectable labeled intermediate ("direct amidification"). The results also show that, in the Trembler mouse sciatic nerves: (a) The severely deficient sphingolipid biosynthesis results from the constitution of a qualitatively and quantitatively abnormal fatty acid substrate pool destined for metabolism via the ceramide pathway, which ensures the totality of the galactocerebroside labeling and two-thirds of that of sphingomyelin. The ceramide intermediates of this pathway are labeled only on their fatty acyl moiety, which contains only 16-carbon atom chains. (b) "Direct amidification" events implicated in sphingolipid labeling are decreased compared with normal and account for the remaining sphingomyelin formation.