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  • Abnormal accumulation and recycling of glycoproteins visualized in Niemann-Pick type C cells using the chemical reporter strategy.

Abnormal accumulation and recycling of glycoproteins visualized in Niemann-Pick type C cells using the chemical reporter strategy.

Proceedings of the National Academy of Sciences of the United States of America (2013-06-05)
Ngalle Eric Mbua, Heather Flanagan-Steet, Steven Johnson, Margreet A Wolfert, Geert-Jan Boons, Richard Steet
RESUMEN

Niemann-Pick type C (NPC) disease is characterized by impaired cholesterol efflux from late endosomes and lysosomes and secondary accumulation of lipids. Although impaired trafficking of individual glycoproteins and glycolipids has been noted in NPC cells and other storage disorders, there is currently no effective way to monitor their localization and movement en masse. Using a chemical reporter strategy in combination with pharmacologic treatments, we demonstrate a disease-specific and previously unrecognized accumulation of a diverse set of glycoconjugates in NPC1-null and NPC2-deficient fibroblasts within endocytic compartments. These labeled vesicles do not colocalize with the cholesterol-laden compartments of NPC cells. Experiments using the endocytic uptake marker dextran show that the endosomal accumulation of sialylated molecules can be largely attributed to impaired recycling as opposed to altered fusion of vesicles. Treatment of either NPC1-null or NPC2-deficient cells with cyclodextrin was effective in reducing cholesterol storage as well as the endocytic accumulation of sialoglycoproteins, demonstrating a direct link between cholesterol storage and abnormal recycling. Our data further demonstrate that this accumulation is largely glycoproteins, given that inhibitors of O-glycan initiation or N-glycan processing led to a significant reduction in staining intensity. Taken together, our results provide a unique perspective on the trafficking defects in NPC cells, and highlight the utility of this methodology in analyzing cells with altered recycling and turnover of glycoproteins.

MATERIALES
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Sigma-Aldrich
Dextran from Leuconostoc spp., Mr ~40,000
Sigma-Aldrich
Dextran from Leuconostoc spp., Mr 450,000-650,000
Sigma-Aldrich
Dextran from Leuconostoc spp., Mr ~70,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 1,500,000-2,800,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 35,000-45,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 60,000-76,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 9,000-11,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 150,000
Supelco
Dextran, analytical standard, for GPC, 25,000
Supelco
Dextran, analytical standard, for GPC, 50,000
Sigma-Aldrich
Dextran solution from Leuconostoc mesenteroides, 20 % (w/w) (Autoclaved)
Supelco
Dextran, analytical standard, for GPC, 5,000
Supelco
Dextran, analytical standard, for GPC, Set Mp 1,000-400,000
Sigma-Aldrich
Dextran from Leuconostoc spp., Mr ~6,000
Supelco
Dextran, analytical standard, for GPC, 270,000
Supelco
Dextran, analytical standard, for GPC, 150,000
Supelco
Dextran, analytical standard, for GPC, 12,000
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, Mr ~200,000
Supelco
Dextran, analytical standard, for GPC, 1,000
Supelco
Dextran, analytical standard, for GPC, 410,000
Supelco
Dextran, analytical standard, for GPC, 80,000
Supelco
Dextran, analytical standard, for GPC, 670,000
Sigma-Aldrich
Dextran from Leuconostoc spp., Mr ~100,000
Supelco
Dextran from Leuconostoc mesenteroides, analytical standard, for GPC, Mw 1,000
Supelco
Dextran from Leuconostoc mesenteroides, analytical standard, for GPC, Mw 5,000
Sigma-Aldrich
Dextran from Leuconostoc spp., Mr 15,000-25,000
Sigma-Aldrich
Dextran, enzymatic synth.
Sigma-Aldrich
Dextran from Leuconostoc mesenteroides, average mol wt 48,000-90,000
Supelco
Dextran from Leuconostoc mesenteroides, analytical standard, for GPC, Mw 670,000
Supelco
Dextran from Leuconostoc mesenteroides, analytical standard, for GPC, Mw 25,000

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