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.
Highlights
Gaucher disease is an autosomal recessive disorder resulting from defective catalytic activity of the lysosomal enzyme, acid b-glucosidase [GCase. glucocerebrosidase, E.C.3.2.1.45]
The results showed that endogenous Ugcg loci and the GCStg (GCS cDNA probe, red) were at different chromosome locations (Fig. 1C)
These mouse models show mild substrate GlcCer accumulation and less severe phenotype compared to their human counterparts [14, 15]
Summary
Gaucher disease is an autosomal recessive disorder resulting from defective catalytic activity of the lysosomal enzyme, acid b-glucosidase [GCase. glucocerebrosidase, E.C.3.2.1.45]. Gaucher disease is an autosomal recessive disorder resulting from defective catalytic activity of the lysosomal enzyme, acid b-glucosidase [GCase. Insufficient GCase activity leads to progressive accumulation of its uncleaved substrates, mainly glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), and a continuum of clinical phenotypes. The most common form in the Western world, Type 1, has visceral involvement; types 2 and 3 have central nervous system (CNS) involvement and are more common outside of the Western world [1,2,3,4,5,6,7,8,9]. The CNS pathogenesis is non-phagocytic and results in neuronal death/drop-out that is thought to be propagated by inflammation and accumulation of the toxic substrates, GlcSph and/or GlcCer [4, 10]
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