| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
Papers In Press, published online ahead of print August 1, 2005
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
Corresponding Author: greg.grabowski{at}cchmc.org
Gaucher disease is a common lysosomal storage disease and caused by defective of acid -glucosidase (GCase). The optimal in vitro hydrolase activity of GCase requires saposin C, an activator protein that derives from a precursor, prosaposin. To develop additional models of Gaucher disease and to test in vivo affects of saposin deficiencies, mice expressing low-levels (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 were designated 4L/PS-NA and 9H/PS-NA, respectively. In contrast to PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed large numbers of engorged macrophages, and nearly exclusive glucosylceramide accumulation in the liver, lung, spleen, thymus, and brain. Electron microscopy of the storage cells showed the characteristic tubular storage material of Gaucher cells. Compared to V394L/V394L mice, 4L/PS-NA mice that expressed 4-6% of wild type prosaposin levels, had ~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.
Revised on July 15, 2005
Accepted on July 21, 2005
Gaucher disease mouse models: Point mutations at the acid
-glucosidase locus combined with low-level prosaposin expression leads to disease variants
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Sun, D. P. Witte, H. Ran, M. Zamzow, S. Barnes, H. Cheng, X. Han, M. T. Williams, M. R. Skelton, C. V. Vorhees, et al. Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice Hum. Mol. Genet., August 1, 2008; 17(15): 2345 - 2356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P Rempel and S. G Withers Covalent inhibitors of glycosidases and their applications in biochemistry and biology Glycobiology, August 1, 2008; 18(8): 570 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, D. P. Witte, M. Zamzow, H. Ran, B. Quinn, J. Matsuda, and G. A. Grabowski Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and {alpha}-hydroxy ceramide accumulation, and altered prosaposin trafficking Hum. Mol. Genet., April 15, 2007; 16(8): 957 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, B. Quinn, Y.-H. Xu, T. Leonova, D. P. Witte, and G. A. Grabowski Conditional expression of human acid {beta}-glucosidase improves the visceral phenotype in a Gaucher disease mouse model J. Lipid Res., October 1, 2006; 47(10): 2161 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Kiss, Z. Ma, K. Nakada-Tsukui, E. Brugnera, G. Vassiliou, H. M. McBride, K. S. Ravichandran, and Y. L. Marcel The Lipoprotein Receptor-related Protein-1 (LRP) Adapter Protein GULP Mediates Trafficking of the LRP Ligand Prosaposin, Leading to Sphingolipid and Free Cholesterol Accumulation in Late Endosomes and Impaired Efflux J. Biol. Chem., April 28, 2006; 281(17): 12081 - 12092. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Journal of Biological Chemistry |
| Molecular and Cellular Proteomics | ASBMB Today |
