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

摘要

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 >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 (644days). 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.