title: Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice.
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 approximately 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.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: te Vruchte
authors.forename: Aruna
authors.initials: A
authors.lastname: Jeans
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Daniel John
authors.initials: DJ
authors.lastname: Sillence
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D006028:Glycosphingolipids / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009844:Oligosaccharides / Q000737:chemistry; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D011961:Receptors, Fc / Q000378:metabolism; D012497:Sandhoff Disease / Q000235:genetics*
chemical_list: D006028:Glycosphingolipids; D009844:Oligosaccharides; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; C035311:immunoglobulin M receptor; D002784:Cholesterol
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