Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease
Date
2016
Authors
Karageorgos, L.
Hein, L.
Rozaklis, T.
Adams, M.
Duplock, S.
Snel, M.
Hemsley, K.
Kuchel, T.
Smith, N.
Hopwood, J.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Neurobiology of Disease, 2016; 91:143-154
Statement of Responsibility
Litsa Karageorgos, Leanne Hein, Tina Rozaklis, Melissa Adams, Stephen Duplock, Marten Snel, Kim Hemsley, Tim Kuchel, Nicholas Smith, John J. Hopwood
Conference Name
Abstract
Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the β-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in β-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000-fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangliosides [GM1, GM2, GM3] concentrations were also detected in the brain. As these glycosphingolipids are involved in many cellular events, an imbalance or disruption of the cell membrane lipid homeostasis would be expected to impair normal neuronal function. To our knowledge, this is the first detailed analysis of glycosphingolipids in various brain regions in a large animal model of neuronal disease, which permits the mechanistic investigation of lipid deregulation and their contribution to neurodegenerative process.
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Dissertation Note
Provenance
Description
Available online 11 March 2016
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© 2016 Elsevier Inc. All rights reserved.