期刊
AUTOPHAGY
卷 9, 期 7, 页码 1115-1116出版社
LANDES BIOSCIENCE
DOI: 10.4161/auto.24919
关键词
saposin; glycosphingolipids; autophagosome; p62; LC3; ubiquitin; lysosome; neurodegeneration
类别
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 -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-beta galactosylceramidase, and globotriaosylceramide to GLA/alpha-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.
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