Journal article
Delineating pathological pathways in a chemically induced mouse model of Gaucher disease
The Journal of Pathology, Vol.239(4), pp.496-509
Aug/2016
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 Gbaflox/flox;nestin‐Cre mouse, with 120 of the 144 genes up‐regulated in CBE‐treated mice also up‐regulated in Gbaflox/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.
Details
- Title
- Delineating pathological pathways in a chemically induced mouse model of Gaucher disease
- Creators
- Ayelet Vardi (null) - 972WIS_INST___112Hila Zigdon (null) - 972WIS_INST___112Anna Meshcheriakova (null) - 972WIS_INST___112Andres David Klein (null) - 972WIS_INST___112Chen Yaacobi (null) - 972WIS_INST___112R Eilam (null) - 972WIS_INST___130Brandon M Kenwood (null) - Georgia Institute of TechnologyAhad A Rahim (null) - University College London (United Kingdom, London) - UCLGiulia Massaro (null) - University College London (United Kingdom, London) - UCLAlfred H. Merrill, Jr. (null) - Georgia Institute of TechnologyEinat Vitner (null) - 972WIS_INST___112Anthony H. Futerman (Corresponding Author) - 972WIS_INST___112
- Resource Type
- Journal article
- Publication Details
- The Journal of Pathology, Vol.239(4), pp.496-509; Aug/2016
- Number of pages
- 14
- Language
- English
- DOI
- https://doi.org/10.1002/path.4751
- Grant note
- This work was supported by an Investigator‐Initiated Research (IIR) grant from Pfizer, by the Minerva Foundation, and by the Children's Gaucher Research Fund. We thank Dr Nicolas Panayotis for help in performing behavioural tests, data analysis, and image preparation; Vladimir Kiss for help with microscopy; Tammar Joseph and Natalia Santos Ferreira for help in performing GCase activity assays; Giora Volpert for help with data analysis; Shifra Ben‐Dor and Irit Orr for help with bioinformatics; and Victoria Korzhova for help with immunohistochemistry. We thank Dr Stefan Karlsson for providing the Gbaflox/flox;nestin‐Cre mice and Dr Simon N Waddington (University College London) for providing the K14‐lnl/lnl mice. AHF is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science. AV and HZ performed most of the experiments and helped with the writing of the manuscript. AM injected mice and performed behavioural tests and immunohistochemistry. ADK performed the gene array. CY and RE performed some of the immunohistochemistry and BMK the mass spectrometry. AAR and GM performed some of the MAC2 immunostaining. AHM directed the mass spectrometry experiments. EBV helped with planning of the experiments. AHF obtained funding of the study, led the research, and wrote the manuscript. Funding Information: Investigator‐Initiated Research (IIR), Minerva Foundation, Children's Gaucher Research Fund.
- Record Identifier
- 993263940003596
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