title: Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.
abstract: In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC–MS/MS, we comparatively investigated the occurrence of abnormal lyso-glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal α-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso-glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in α-galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase-deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ferraz
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands.
authors.forename: André R A
authors.initials: AR
authors.lastname: Marques
authors.affiliation: Organelle Biogenesis & Function Group, Instituto de Investigação e Inovação em Saúde (I3S), 4200-135 Porto, Portugal; Lysosome and Peroxisome Biology Unit (UniLiPe), Institute of Molecular and Cell Biology (IBMC), Universidade do Porto, 4150-180 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Gaspar
authors.affiliation: Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands.
authors.forename: Mina
authors.initials: M
authors.lastname: Mirzaian
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands.
authors.forename: Cindy
authors.initials: C
authors.lastname: van Roomen
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands.
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Translacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alfonso
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Translacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Irún
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Translacional, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wisse
authors.affiliation: Organelle Biogenesis & Function Group, Instituto de Investigação e Inovação em Saúde (I3S), 4200-135 Porto, Portugal; Lysosome and Peroxisome Biology Unit (UniLiPe), Institute of Molecular and Cell Biology (IBMC), Universidade do Porto, 4150-180 Porto, Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Sá Miranda
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands; Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands. Electronic address: j.m.f.g.aerts@lic.leidenuniv.nl.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D005260:Female; D006028:Glycosphingolipids / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013261:Sterols / Q000097:blood
chemical_list: D006028:Glycosphingolipids; D013261:Sterols
keywords: Fabry disease; Gaucher disease; Glycosphingoid bases; Glycosphingolipid; LC–MS/MS; Mouse models; Niemann–Pick type C