title: Tissue-specific effects of saposin A and saposin B on glycosphingolipid degradation in mutant mice.
abstract: 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 (~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.
authors: The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. ying.sun@cchmc.org
authors: Ying
authors: Y
authors: Sun
authors: Matt
authors: M
authors: Zamzow
authors: Huimin
authors: H
authors: Ran
authors: Wujuan
authors: W
authors: Zhang
authors: Brian
authors: B
authors: Quinn
authors: Sonya
authors: S
authors: Barnes
authors: David P
authors: DP
authors: Witte
authors: Kenneth D R
authors: KD
authors: Setchell
authors: Michael T
authors: MT
authors: Williams
authors: Charles V
authors: CV
authors: Vorhees
authors: Gregory A
authors: GA
authors: Grabowski
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D005698:Galactosylceramidase / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009422:Nervous System Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D009928:Organ Specificity; D010641:Phenotype; D049231:Saposins / Q000172:deficiency* / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D049231:Saposins; C021502:acid beta-galactosidase; D001616:beta-Galactosidase; D005698:Galactosylceramidase