The function of sphingolipids in the nervous system: lessons learnt from mouse models of specific sphingolipid activator protein deficiencies.

We have generated specific saposin A and D deficient mouse mutants by the gene targeting technology. Saposin A deficient mice showed the clinical, biochemical and pathological phenotype of a chronic form of globoid cell leukodystrophy (Krabbe disease) establishing that saposin A is essential for in vivo degradation of galactosylceramide. Saposin D deficient mice showed an accumulation of ceramides containing alpha-hydroxy fatty acids (HFA/d18:1) in the brain and kidney and showed renal tubular degeneration and cerebellar Purkinje cell loss. Here we review the current information which we have learnt from these mouse models of specific sphingolipid activator protein deficiencies. Collectively, the information provides support for the potential importance of sphingolipids in the function of the nervous system.