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A modified lipid composition in Fabry disease leads to an intracellular block of the detergent‐resistant membrane‐associated dipeptidyl peptidase IV
Author(s) -
Maalouf Katia,
Jia Jia,
Rizk Sandra,
Brogden Graham,
Keiser Markus,
Das Anibh,
Naim Hassan Y.
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/s10545-010-9114-6
Subject(s) - fabry disease , intracellular , lipid microdomain , lipid raft , membrane protein , biochemistry , microbiology and biotechnology , biology , dipeptidyl peptidase , glycolipid , sorting nexin , cell membrane , cell , membrane , chemistry , enzyme , medicine , endosome , disease
Fabry disease is an X‐linked lysosomal storage disorder that leads to abnormal accumulation of glycosphingolipids due to a deficiency of alpha‐galactosidase A (AGAL). The consequences of these alterations on the targeting of membrane proteins are poorly understood. Glycosphingolipids are enriched in Triton‐X‐100‐ resistant lipid rafts [detergent‐resistant membranes (DRMs)] and play an important role in the transport of several membrane‐associated proteins. Here, we show that In fibroblasts of patients suffering from Fabry disease, the colocalization of AGAL with the lysosomal marker LAMP2 is decreased compared with wild‐type fibroblasts concomitant with a reduced transport of AGAL to lysosomes. Furthermore, overall composition of membrane lipids in the patients’ fibroblasts as well as in DRMs reveals a substantial increase in the concentration of glycolipids and a slight reduction of phosphatidylethanolamine (PE). The altered glycolipid composition in Fabry fibroblasts is associated with an intracellular accumulation and impaired trafficking of the Triton‐X‐100 DRM‐associated membrane glycoprotein dipeptidyl peptidase IV (DPPIV) in transfected Fabry cells, whereas no effect could be observed on the targeting of aminopeptidase N (ApN) that is not associated with this type of DRM. We propose that changes in the lipid composition of cell membranes in Fabry disease disturb the ordered Triton X‐100 DRMs and have implications on the trafficking and sorting of DRM‐associated proteins and the overall protein–lipid interaction at the cell membrane. Possible consequences could be altered signalling at the cell surface triggered by DRM‐associated proteins, with implications on gene regulation and subsequent protein expression.