title: Altered autophagy in the mice with a deficiency of saposin A and saposin B.
abstract: 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.
authors.affiliation: Division of Human Genetics; Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine; Cincinnati, OH USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D049231:Saposins / Q000172:deficiency* / Q000378:metabolism*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D049231:Saposins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C587505:saposin A, mouse; C587506:saposin B, mouse
keywords: LC3; autophagosome; glycosphingolipids; lysosome; neurodegeneration; p62; saposin; ubiquitin