TY - JOUR
T1 - Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease
AU - Karageorgos, Litsa
AU - Hein, Leanne
AU - Rozaklis, Tina
AU - Adams, Melissa
AU - Duplock, Stephen
AU - Snel, Marten
AU - Hemsley, Kim
AU - Kuchel, Tim
AU - Smith, Nicholas
AU - Hopwood, John J.
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
KW - Gangliosides
KW - Glucocerebrosidase
KW - Glucosylceramide
KW - Lipid metabolism
KW - Sheep model
KW - Sphingolipids
UR - http://www.scopus.com/inward/record.url?scp=84961141313&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2016.03.011
DO - 10.1016/j.nbd.2016.03.011
M3 - Article
C2 - 26976737
AN - SCOPUS:84961141313
VL - 91
SP - 143
EP - 154
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -