Vardi, A;
Zigdon, H;
Meshcheriakova, A;
Klein, AD;
Yaacobi, C;
Eilam, R;
Kenwood, BM;
... Futerman, AH; + view all
(2016)
Delineating pathological pathways in a chemically-induced mouse model of Gaucher disease.
The Journal of Pathology
, 239
(4)
pp. 496-509.
10.1002/path.4751.
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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 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 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 behavioral 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.
| Type: | Article |
|---|---|
| Title: | Delineating pathological pathways in a chemically-induced mouse model of Gaucher disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/path.4751 |
| Publisher version: | http://dx.doi.org/10.1002/path.4751 |
| Language: | English |
| Additional information: | Copyright © Pathological Society of Great Britain and Ireland, first published by John Wiley & Sons Ltd. This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at http://dx.doi.org/10.1002/path.4751. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. |
| Keywords: | Gaucher disease, Parkinson's disease, acid β-glucosidase, glucosylceramide, glucosylsphingosine, neuroinflammation, neuropathology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1498984 |
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