Abstract |
Gaucher disease is a lysosomal storage disease caused by defective activity of acid β- glucosidase (GCase), which leads to the accumulation of its major substrates, glucosylceramide (GlcCer) and glucosylsphingosine ( GlcSph) in many cells. To modulate cellular substrate concentration in viable mouse models of Gaucher disease (Gba1 mutants), a novel mouse model was created with enhanced glycosphingolipid biosynthesis. This was accomplished by cross-breeding Gba1 mutant mice with mice expressing a transgene (GCStg) containing the mouse glucosylceramide synthase (GCS, Ugcg) cDNA driven by the ROSA promoter, yielding GCStg/Gba1 mice. The GCStg rescued Ugcg null mice from embryonic lethality. GCStg/Gba1 mice showed 2-3 fold increases in tissue GCS activity as well as accelerated GlcCer accumulation and the appearance of lipid-laden CD68 positive macrophages in visceral organs. Although GlcCer/ GlcSph concentrations were elevated in the brain, there was no neurodegenerative phenotype up to 1 yr of age conceivably due to the greater residual GCase hydrolytic activity in the brains than in the visceral tissues of 9V/null mice. These studies provide 'proof of principle' for threshold substrate flux that modifies phenotypic development in Gaucher disease and other lysosomal storage diseases.
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Authors | Sonya Barnes, You-Hai Xu, Wujuan Zhang, Benjamin Liou, Kenneth D R Setchell, Liming Bao, Gregory A Grabowski, Ying Sun |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 12
Pg. e116023
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 25551612
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antigens, CD
- Antigens, Differentiation, Myelomonocytic
- CD68 protein, mouse
- Glucosylceramides
- Glucosyltransferases
- ceramide glucosyltransferase
- Glucosylceramidase
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Topics |
- Animals
- Antigens, CD
(metabolism)
- Antigens, Differentiation, Myelomonocytic
(metabolism)
- Disease Models, Animal
- Gaucher Disease
(enzymology, pathology)
- Glucosylceramidase
(biosynthesis, genetics)
- Glucosylceramides
(biosynthesis, metabolism)
- Glucosyltransferases
(genetics)
- Macrophages
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Promoter Regions, Genetic
(genetics)
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