Combined saposin A and saposin B deficiency (AB(-/-)) was created in mice by knock-in of point mutations into the saposin A and B domains of the Psap (encoding prosaposin) locus. PSAP is the precursor of saposin A, saposin B and two other members, saposin C and saposin D. Those four saposins have multiple functions including their roles as glycosphingolipid activator proteins in a lysosomal glycosphingolipid degradation pathway. Saposin A participates in the removal of galactose from galactosylceramide and galactosylsphingosine by enhancing β-galactosylceramidase activity. Saposin B has lipid binding properties and is involved in glycosphingolipid metabolism by presenting the substrates to specific enzymes for degradation, i.e., sulfatide to ARSA/arylsulfatase A, lactosylceramide to GALC/GM-1-β-galactosylceramidase, and globotriaosylceramide to GLA/α-galactosidase. Galactosylceramide and sulfatide are myelin glycosphingolipids involved in carbohydrate interaction between synapses. The AB(-/-) mice develop accumulation of multiple glycosphingolipids in various organs. Sulfatide and galactosylsphingosine, a deacylated form of galactosylceramide, are the major substrates accumulated in the CNS of AB(-/-) mice. The latter is a toxic metabolite to oligodendrocytes and results in demyelination and cell death.