title: Specific downregulation and mistargeting of the lipid raft-associated protein MAL in a glycolipid storage disorder.
abstract: Metachromatic leukodystrophy (MLD) is a lysosomal lipid storage disease caused by arylsulfatase A deficiency. In MLD patients the sphingolipid sulfatide increasingly accumulates leading to progressive demyelination. We have analysed arylsulfatase A-deficient mice, a MLD mouse model, and we show that accumulation of sulfatide is not restricted to the lysosomal compartment but also occurs in myelin itself. Although, this sulfatide storage did not affect the overall composition of most myelin proteins, it specifically caused a severe reduction of MAL. This demonstrates a regulatory link between sulfatide accumulation and MAL expression and indicates the existence of regulatory mechanisms between lipid and myelin protein synthesis in oligodendrocytes. In addition, in cultured renal epithelial cells, sulfatide accumulation diverts MAL to the late endosomal/lysosomal compartment and thus also affects the intracellular distribution of MAL. The specific reduction and mistargeting of MAL protein as a reaction to sulfatide overload may contribute to the pathogenic mechanisms in metachromatic leukodystrophy.
authors.affiliation: Institute of Physiological Chemistry, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Saravanan
authors.forename: N
authors.initials: N
authors.lastname: Schaeren-Wiemers
authors.forename: D
authors.initials: D
authors.lastname: Klein
authors.forename: R
authors.initials: R
authors.lastname: Sandhoff
authors.forename: A
authors.initials: A
authors.lastname: Schwarz
authors.forename: A
authors.initials: A
authors.lastname: Yaghootfam
authors.forename: V
authors.initials: V
authors.lastname: Gieselmann
authors.forename: S
authors.initials: S
authors.lastname: Franken
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002553:Cerebroside-Sulfatase / Q000235:genetics*; D003902:Detergents; D015536:Down-Regulation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007966:Leukodystrophy, Metachromatic / Q000378:metabolism* / Q000503:physiopathology*; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids / Q000235:genetics* / Q000378:metabolism*; D013433:Sulfoglycosphingolipids / Q000378:metabolism
chemical_list: D003902:Detergents; C569027:Mal protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D013433:Sulfoglycosphingolipids; D002553:Cerebroside-Sulfatase