A modified lipid composition in Fabry's disease leads to an intracellular block of the lipid rafts‐associated dipeptidylpeptidase IV

Abstract

Fabry's disease (Anderson‐Fabry's disease) is an X‐linked lysosomal storage disorder caused by deficiency of á‐galactosidase A (AGAL), and results in an abnormal accumulation of glycosphingolipids. Here, we show by confocal laser microscopy of Fabry fibroblasts that the colocalization of AGAL with the lysosomal marker LAMP2 is decreased concomitant with a reduced transport of AGAL to lysosomes. Furthermore, analysis of overall composition of membrane lipids in the patients' fibroblasts reveals altered concentrations of glycolipids and phosphatidylethanolamine (PE). The consequences are (i) a decrease in the concentration of lipid rafts as assessed by the reduced levels of the rafts marker flotillin2 in the floating fractions of sucrose gradients of Triton X‐100 lysates of Fabry fibroblasts and (ii) intracellular block and impaired trafficking of lipid rafts‐associated glycoproteins, such as dipeptidyl peptidase IV. The intracellular transport of proteins that are not associated with lipid rafts, such as aminopeptidase N, is not affected. Therefore, the impaired trafficking of AGAL is not only associated with altered glycolipid structure, but elicits also causal effects related to protein trafficking and sorting.