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Gaucher disease mouse models: point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants

Sun, Ying, Quinn, Brian, Witte, David P., Grabowski, Gregory A.·2005·Journal of Lipid Research
DOI 10.1194/jlr.m500202-jlr200
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PS-NA WT PS-NA WTPS-NA WT
PS-NA WT PS-NA WTPS-NA WTCC-BY · From the PDF
Image 2
CC-BY · From the PDF
Fig. 2 Storage cells in the visceral tissues of age-matched (22 weeks) PS-NA, 4L/PS-NA, and 9H/PS-NA mice. Hematoxylin and eosin-stained sections of liver, spleen, and lung from PS-NA mice had a normal appearance. In comparison, clusters of lipid storage cells (arrows) were observed in 4L/PS-NA and 9H/PS-NA liver and spleen. Engorged storage cells (arrows) also were present in alveolar and interstitial spaces of the lungs of these mice. Magnifications are 400 × .
Fig. 2 Storage cells in the visceral tissues of age-matched (22 weeks) PS-NA, 4L/PS-NA, and 9H/PS-NA mice. Hematoxylin and eosin-stained sections of liver, spleen, and lung from PS-NA mice had a normal appearance. In comparison, clusters of lipid storage cells (arrows) were observed in 4L/PS-NA and 9H/PS-NA liver and spleen. Engorged storage cells (arrows) also were present in alveolar and interstitial spaces of the lungs of these mice. Magnifications are 400 × .CC-BY · From the PDF
Fig. 3 Electron micrographs of inclusions in 4L/PS-NA mouse lungs. Storage bodies in lung (A; 8,000 × ) had a characteristic braided structure of glucosylceramide (GC), as observed in Gaucher disease. An enlarged view of the storage bodies is shown in B.
Fig. 3 Electron micrographs of inclusions in 4L/PS-NA mouse lungs. Storage bodies in lung (A; 8,000 × ) had a characteristic braided structure of glucosylceramide (GC), as observed in Gaucher disease. An enlarged view of the storage bodies is shown in B.CC-BY · From the PDF
Fig. 4 CD68 staining of cells in the visceral tissues from WT, 4L/PS-NA, and 9H/PS-NA mice. A: Frozen tissue sections from various mice were stained with anti-CD68 (rat anti-mouse) monoclonal antibody (black) and counterstained with methylene green for cell nuclei. Very few CD68-positive cells were in WT spleen, liver, and lung or such tissues from PS-NA mice (not shown). CD68-positive cells were present in large numbers in spleen, liver, and lung of 4L/PS-NA and 9H/PS-NA mice. Magnifications are 400 × . B: Frozen tissue sections from 4L/PSNA mice were stained with periodic acid-Schiff (PAS) and CD68. The periodic acid-Schiff-positive storage cells (arrows) in liver and lung also were CD68-positive, indicating that they were macrophage-derived.
Fig. 4 CD68 staining of cells in the visceral tissues from WT, 4L/PS-NA, and 9H/PS-NA mice. A: Frozen tissue sections from various mice were stained with anti-CD68 (rat anti-mouse) monoclonal antibody (black) and counterstained with methylene green for cell nuclei. Very few CD68-positive cells were in WT spleen, liver, and lung or such tissues from PS-NA mice (not shown). CD68-positive cells were present in large numbers in spleen, liver, and lung of 4L/PS-NA and 9H/PS-NA mice. Magnifications are 400 × . B: Frozen tissue sections from 4L/PSNA mice were stained with periodic acid-Schiff (PAS) and CD68. The periodic acid-Schiff-positive storage cells (arrows) in liver and lung also were CD68-positive, indicating that they were macrophage-derived.CC-BY · From the PDF
Image 6
CC-BY · From the PDF
Fig. 6 GC accumulation in 4L/PS-NA and 9H/PS-NA mice. A: Typical TLC of lipid analyses showing increased GC accumulation in 4L/ PS-NA tissues compared with PS-NA mice at 12 weeks (left panel). In 9H/PS-NA mice (18 weeks), GC accumulation was increased in liver compared with PS-NA mice at 21 weeks (right panel). Brain refers to a cerebellar hemisphere. The other lipids were unchanged from PSNA. GalCer, galactosylceramide; LacCer, lactosylceramide; Sphing, sphingomyelin; TriCer, globotriaosylceramide. B: Progressive accumulation of GC with age in 4L/PS-NA tissues compared with PS-NA mice at 20 weeks. Extractions of each tissue from three mice at each age were analyzed. The amount of GC in each tissue was quantitated by densitometric scanning relative to the GC duplicate standards for each mouse.
Fig. 6 GC accumulation in 4L/PS-NA and 9H/PS-NA mice. A: Typical TLC of lipid analyses showing increased GC accumulation in 4L/ PS-NA tissues compared with PS-NA mice at 12 weeks (left panel). In 9H/PS-NA mice (18 weeks), GC accumulation was increased in liver compared with PS-NA mice at 21 weeks (right panel). Brain refers to a cerebellar hemisphere. The other lipids were unchanged from PSNA. GalCer, galactosylceramide; LacCer, lactosylceramide; Sphing, sphingomyelin; TriCer, globotriaosylceramide. B: Progressive accumulation of GC with age in 4L/PS-NA tissues compared with PS-NA mice at 20 weeks. Extractions of each tissue from three mice at each age were analyzed. The amount of GC in each tissue was quantitated by densitometric scanning relative to the GC duplicate standards for each mouse.CC-BY · From the PDF
Fig. 7 Acid 𝛃 -glucosidase (GCase) activity and protein levels in 4L/PS-NA mouse tissues. A: In liver and spleen, GCase activities were decreased significantly in 4L/PS-NA mice compared with V394L/V394L mice. GCase activities in lung and brain were unchanged in 4L/PSNA and PS-NA mice. ** P < 0.01, *** P < 0.001 (for comparison of V394L/V394L with 4L/PS-NA tissues; n = 3-5). B: Relative GCase activity and protein levels in cultured fibroblasts. The bar indicates that GCase activities were significantly decreased in 4L/PS-NA cells compared with V394L/V394L. ** P < 0.01 (for comparison of V394L/V394L with 4L/PS-NA cells; n = 3). The bottom panel shows that GCase protein (Mr H11601 60,000) in fibroblasts was detected using rabbit anti-mouse GCase antibody. 𝛃 -Actin was the loading control. Quantitation was performed with Molecular Dynamics ImageQuant Software using the ratio of GCase/ 𝛃 -actin for normalization. GCase protein levels in PS-NA, 4L/PS-NA, and V394L fibroblasts are presented as percentages of WT levels. Each experiment was repeated in triplicate.
Fig. 7 Acid 𝛃 -glucosidase (GCase) activity and protein levels in 4L/PS-NA mouse tissues. A: In liver and spleen, GCase activities were decreased significantly in 4L/PS-NA mice compared with V394L/V394L mice. GCase activities in lung and brain were unchanged in 4L/PSNA and PS-NA mice. ** P < 0.01, *** P < 0.001 (for comparison of V394L/V394L with 4L/PS-NA tissues; n = 3-5). B: Relative GCase activity and protein levels in cultured fibroblasts. The bar indicates that GCase activities were significantly decreased in 4L/PS-NA cells compared with V394L/V394L. ** P < 0.01 (for comparison of V394L/V394L with 4L/PS-NA cells; n = 3). The bottom panel shows that GCase protein (Mr H11601 60,000) in fibroblasts was detected using rabbit anti-mouse GCase antibody. 𝛃 -Actin was the loading control. Quantitation was performed with Molecular Dynamics ImageQuant Software using the ratio of GCase/ 𝛃 -actin for normalization. GCase protein levels in PS-NA, 4L/PS-NA, and V394L fibroblasts are presented as percentages of WT levels. Each experiment was repeated in triplicate.CC-BY · From the PDF

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Metadata

Authors
Sun, Y., Quinn, B., Witte, D. P., & Grabowski, G. A.
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2005-10
Volume
46
Issue
10
Pages
2102-2113
ISSN
0022-2275
DOI
10.1194/jlr.m500202-jlr200
Cited by
72
References
0
Language
en
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CoChat. (2026). Citation check: Gaucher disease mouse models: point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants. https://app.cochat.ai/papers/10.1194/jlr.m500202-jlr200
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Sun, Y., Quinn, B., Witte, D. P., & Grabowski, G. A. (2005). Gaucher disease mouse models: point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants. Journal of Lipid Research. https://doi.org/10.1194/jlr.m500202-jlr200