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Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice
Author(s) -
Vruchte Danielle,
Jeans Aruna,
Platt Frances M.,
Sillence Daniel John
Publication year - 2010
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-010-9109-3
Subject(s) - sandhoff disease , glycosphingolipid , biology , globotriaosylceramide , receptor , ganglioside , lysosomal storage disease , microbiology and biotechnology , biochemistry , medicine , fabry disease , disease , enzyme
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.