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Mol Genet Metab. 2016 Feb;117(2):186-93. doi: 10.1016/j.ymgme.2015.12.006. Epub 2015 Dec 23.

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.

Author information

1
Department of Medical Biochemistry, Academic Medical Center, 1105, AZ, Amsterdam, The Netherlands.
2
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.
3
Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands.
4
Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad de Investigación Translacional, Zaragoza, Spain.
5
Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2333, CC, Leiden, The Netherlands.
6
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.
7
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.

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.

KEYWORDS:

Fabry disease; Gaucher disease; Glycosphingoid bases; Glycosphingolipid; LC–MS/MS; Mouse models; Niemann–Pick type C

PMID:
26750750
DOI:
10.1016/j.ymgme.2015.12.006
[Indexed for MEDLINE]

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