标题：Gaucher disease mouse models: point mutations at the acid {beta}-glucosidase locus combined with low-level prosaposin expression lead to disease variants
出版社：American Society for Biochemistry and Molecular Biology
摘要：Gaucher disease is a common lysosomal storage disease causedby a defect of acid ß-glucosidase (GCase). The optimalin vitro hydrolase activity of GCase requires saposin C, anactivator protein that derives from a precursor, prosaposin.To develop additional models of Gaucher disease and to testin vivo effects of saposin deficiencies, mice expressing lowlevels (4–45% of wild type) of prosaposin and saposins(PS-NA) were backcrossed into mice with specific point mutations(V394L/V394L or D409H/D409H) of GCase. The resultant mice weredesignated 4L/PS-NA and 9H/PS-NA, respectively. In contrastto PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed largenumbers of engorged macrophages and nearly exclusive glucosylceramide(GC) accumulation in the liver, lung, spleen, thymus, and brain.Electron microscopy of the storage cells showed the characteristictubular storage material of Gaucher cells. Compared with V394L/V394Lmice, 4L/PS-NA mice that expressed 4–6% of wild-type prosaposinlevels had 25–75% decreases in GCase activity and proteinin liver, spleen, and fibroblasts.
These results imply that reduced saposin levels increased theinstability of V394L or D409H GCases and that these additionaldecreases led to large accumulations of GC in all tissues. Thesemodels mimic a more severe Gaucher disease phenotype and couldbe useful for therapeutic intervention studies.Abbreviations: CNS, central nervous system; gba, gene encoding mouse acid ß-glucosidase; GC, glucosylceramide; GCase, acid ß-glucosidase; LacCer, lactosylceramide; 4MU-Glc, 4-methylumbelliferyl-ß-D-glucopyranoside; WT, wild-type
Supplementary key words macrophage • lysosomal storage disease • glycosphingolipids
25–75% decreases in GCase activity and protein in liver, spleen, and fibroblasts.
These results imply that reduced saposin levels increased the instability of V394L or D409H GCases and that these additional decreases led to large accumulations of GC in all tissues. These models mimic a more severe Gaucher disease phenotype and could be useful for therapeutic intervention studies.
Abbreviations: CNS, central nervous system; gba, gene encoding mouse acid ß-glucosidase; GC, glucosylceramide; GCase, acid ß-glucosidase; LacCer, lactosylceramide; 4MU-Glc, 4-methylumbelliferyl-ß-D-glucopyranoside; WT, wild-type
Supplementary key words macrophage • lysosomal storage disease • glycosphingolipids
