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Individual saposin A (A−/−) and saposin B (B−/−)-deficient mice show unique phenotypes caused by insufficient degradation of myelin-related glycosphingolipids (GSLs): galactosylceramide and galactosylsphingosine and sulfatide, respectively. To gain insight into the interrelated functions of saposins A and B, combined saposin AB-deficient mice (AB−/−) were created by knock-in point mutations into the saposins A and B domains on the prosaposin locus. Saposin A and B proteins were undetectable in AB−/− mice, whereas prosaposin, saposin C and saposin D were expressed near wild-type (WT) levels. AB−/− mice developed neuromotor deterioration at &gt;61 days and exhibited abnormal locomotor activity and enhanced tremor. AB−/− mice (∼96 days) lived longer than A−/− mice (∼85 days), but shorter than B−/− mice (∼644 days). Storage materials were observed in Schwann cells and neuronal processes by electron microscopy. Accumulation of p62 and increased levels of LC3-II were detected in the brainstem suggesting altered autophagy. GSL analyses by (liquid chromatography) LC/MS identified substantial increases in lactosylceramide in AB−/− mouse livers. Sulfatide accumulated, but galactosylceramide remained at WT levels, in the AB−/− mouse brains and kidneys. Brain galactosylsphingosine in AB−/− mice was ∼68% of that in A−/− mice. These findings indicate that combined saposins A and B deficiencies attenuated GalCer-β-galactosylceramidase and GM1-β-galactosidase functions in the degradation of lactosylceramide preferentially in the liver. Blocking sulfatide degradation from the saposin B deficiency diminished galactosylceramide accumulation in the brain and kidney and galctosylsphingosine in the brain. These analyses of AB−/− mice continue to delineate the tissue differential interactions of saposins in GSL metabolism.

Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice