期刊
HUMAN MOLECULAR GENETICS
卷 22, 期 12, 页码 2435-2450出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt096
关键词
-
资金
- [R01 NS/DK 36681]
- [DK 36729]
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--galactosylceramidase and GM1--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.
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