title: Delineating pathological pathways in a chemically induced mouse model of Gaucher disease.
abstract: Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently discovered genetic relationship with Parkinson's disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor conduritol B-epoxide (CBE) is particularly attractive, although few systematic studies examining the effect of CBE on the development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on both the levels of accumulated lipids and the time at which their accumulation begins. Gene array analysis shows a remarkable similarity in the gene expression profiles of CBE-treated mice and a genetic GD mouse model, the Gba(flox/flox) ;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up-regulated in Gba(flox/flox) ;nestin-Cre mice. We also demonstrate that various aspects of neuropathology and some behavioural abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD. This is particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time-consuming crossing of mice. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Vardi
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Zigdon
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Meshcheriakova
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Andrés D
authors.initials: AD
authors.lastname: Klein
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Yaacobi
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.affiliation: School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Kenwood
authors.affiliation: Department of Pharmacology, School of Pharmacy, University College London, London, UK.
authors.forename: Ahad A
authors.initials: AA
authors.lastname: Rahim
authors.affiliation: Department of Pharmacology, School of Pharmacy, University College London, London, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Massaro
authors.affiliation: School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Einat B
authors.initials: EB
authors.lastname: Vitner
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D020869:Gene Expression Profiling; D007294:Inositol / Q000031:analogs & derivatives; D051379:Mice
chemical_list: D007294:Inositol; C011423:conduritol epoxide
keywords: Gaucher disease; Parkinson's disease; acid β-glucosidase; glucosylceramide; glucosylsphingosine; neuroinflammation; neuropathology