A Mutation in the Saposin C Domain of the Sphingolipid Activator Protein (Prosaposin) Gene Causes Neurodegenerative Disease in Mice

Saposins A, B, C, and D are small amphiphatic glycoproteins that are encoded in tandem within a precursor protein (prosaposin, PSAP), and are required for in vivo degradation of sphingolipids. Humans with saposin C deficiency exhibit the clinical presentation of Gaucher-like disease. We generated two types of saposin C mutant mice, one carrying a homozygous missense mutation (C384S) in the saposin C domain of prosaposin (Sap-C-/-) and the other carrying the compound heterozygous mutation with a second null Psap allele (Psap(-/C384S)). During early life stages, both Sap-C-/- and Psap(-/C384S) mice grew normally; however, they developed progressive motor and behavioral deficits after 3 months of age and the majority of affected mice could scarcely move by about 15 months. They showed no signs of hepatosplenomegaly throughout their lives. No accumulation of glucosylceramide and glucosylsphingosine was detected in the brain or liver of both Sap-C-/- and Psap(-/C384S) mice. Neuropathological analyses revealed patterned loss of cerebellar Purkinje cells, widespread axonal spheroids filled with membrane-derived concentric or lamellar electron-dense bodies, and lipofuscin-like deposition in the neurons. Soap-bubble-like inclusion bodies were detected in the trigeminal ganglion cells and the vascular endothelial cells. Compound heterozygous Psap(-/C384S) mice showed qualitatively identical but faster progression of the neurological phenotypes than Sap-C-/- mice. These results suggest the in vivo role of saposin C in axonal membrane homeostasis, the disruption of which leads to neurodegeneration in lysosomal storage disease. (C) 2010 Wiley-Liss, Inc.