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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.

plos one

Ubiquitous Transgene Expression of the Glucosylceramide-Synthesizing Enzyme Accelerates Glucosylceramide Accumulation and Storage Cells in a Gaucher Disease Mouse Model