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Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice

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Journal of Inherited Metabolic Disease

Abstract

Glycosphingolipid storage diseases are a group of inherited metabolic diseases in which glycosphingolipids accumulate due to their impaired lysosomal breakdown. Splenic B cells isolated from NPC1, Sandhoff, GM1-gangliosidosis and Fabry disease mouse models showed large (20- to 30-fold) increases in disease specific glycosphingolipids and up to a 4-fold increase in cholesterol. The magnitude of glycosphingolipid storage was in the order NPC1 > Sandhoff ∼ GM1 gangliosidosis > Fabry. Except for Fabry disease, glycosphingolipid storage led to an increase in the lysosomal compartment and altered glycosphingolipid trafficking. In order to investigate the consequences of storage on B cell function, the levels of surface expression of B cell IgM receptor and its associated components were quantitated in Sandhoff B cells, since they are all raft-associated on activation. Both the B cell receptor, CD21 and CD19 had decreased cell surface expression. In contrast, CD40 and MHC II, surface receptors that do not associate with lipid rafts, were unchanged. Using a pulse chase biotinylation procedure, surface B cell receptors on a Sandhoff lymphoblast cell line were found to have a significantly decreased half-life. Increased co-localization of fluorescently conjugated cholera toxin and lysosomes was also observed in Sandhoff B cells. Glycosphingolipid storage leads to the enhanced formation of lysosomal lipid rafts, altered endocytic trafficking and increased degradation of the B cell receptor.

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Acknowledgements

Action Medical Research and the Ara Parseghian Foundation for Medical Research funded this study. The flow cytometry instrument was funded by The Wellcome Trust (084631).

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  1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

    Danielle te Vruchte, Aruna Jeans & Frances M. Platt

  2. Cell Signalling Lab, Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK

    Daniel John Sillence

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  1. Danielle te Vruchte
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  2. Aruna Jeans
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Correspondence to Daniel John Sillence.

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Communicated by: Douglas A. Brooks

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te Vruchte, D., Jeans, A., Platt, F.M. et al. Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice. J Inherit Metab Dis 33, 261–270 (2010). https://doi.org/10.1007/s10545-010-9109-3

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