The role of saposin C in Gaucher disease

Abstract

Saposin C is one of four homologous proteins derived from sequential cleavage of the saposin precursor protein, prosaposin. It is an essential activator for glucocerebrosidase, the enzyme deficient in Gaucher disease. Gaucher disease is a rare autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene that exhibits vast phenotypic heterogeneity, despite its designation as a "simple" Mendelian disorder. The observed phenotypic variability has led to a search for disease modifiers that can alter the Gaucher phenotype. The PSAP gene encoding saposin C is a prime candidate modifier for Gaucher disease. In humans, saposin C deficiency due to mutations in PSAP results in a Gaucher-like phenotype, despite normal in vitro glucocerebrosidase activity. Saposin C deficiency has also been shown to modify phenotype in one mouse model of Gaucher disease. The role of saposin C as an activator required for normal glucocerebrosidase function, and the consequences of saposin C deficiency are described, and are being explored as potential modifying factors in patients with Gaucher disease.

Fig. 1

Prosaposin cDNA structure, with individual saposin domains noted. The 16-amino acid signal peptide is shaded in red, and functional saposin domains are shown in blue. Cysteine residues and glycosylation sites are indicated.

Fig. 2

Amino acid sequence of saposin C. The three conserved disulfide linkages are underlined and bolded, along with the N-glycosylation site (red).

Fig. 3

Proposed mechanisms of GCase (orange) activation by Sap C (blue). Sap C embeds in preexisting defects in the bilayer membrane, resulting in a thinned membrane domain, and exposing the headgroup of glucocerebroside substrate (purple ball). Activated GCases is shown in red. a) Solubilizer model. Sap C dissociates from the membrane in a soluble complex with glucocerebroside, which is hydrolyzed by GCase in solution. b) Liftase model. Sap C stably associates with the membrane and exposes glucocerebroside for direct hydrolysis by GCase on the surface of thinned membrane domains.