title: Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease.
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.
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia. Electronic address: litsa.karageorgos@sahmri.com.
authors.forename: Litsa
authors.initials: L
authors.lastname: Karageorgos
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Leanne
authors.initials: L
authors.lastname: Hein
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Rozaklis
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Adams
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Duplock
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Marten
authors.initials: M
authors.lastname: Snel
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Hemsley
authors.affiliation: Preclinical Imaging and Research Laboratories, South Australian Health and Medical Research Institute, South Australia 5001, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Kuchel
authors.affiliation: Department of Neurology, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Smith
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia 5001, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism*; D006028:Glycosphingolipids / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D012756:Sheep; D013154:Spleen / Q000378:metabolism
chemical_list: D005963:Glucosylceramides; D006028:Glycosphingolipids
keywords: Gangliosides; Glucocerebrosidase; Glucosylceramide; Lipid metabolism; Sheep model; Sphingolipids