title: A modified lipid composition in Fabry disease leads to an intracellular block of the detergent-resistant membrane-associated dipeptidyl peptidase IV.
abstract: 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.
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine, Buenteweg 17, 30559, Hannover, Germany.
authors.forename: Katia
authors.initials: K
authors.lastname: Maalouf
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Sandra
authors.initials: S
authors.lastname: Rizk
authors.forename: Graham
authors.initials: G
authors.lastname: Brogden
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
authors.forename: Anibh
authors.initials: A
authors.lastname: Das
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
mesh_terms: D018929:Cell Culture Techniques; D003902:Detergents / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D017830:Octoxynol / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D003902:Detergents; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D013107:Sphingolipids; D017830:Octoxynol; D000519:alpha-Galactosidase; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4