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 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.

Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease

“…These mice were injected intraperitoneally with conduritol b-epoxide (CBE) (Calbiochem Millipore, Darmstadt, Germany), a GCase inhibitor. CBE has been used to induce GD in various mouse strains [13], and the pathology is remarkably similar to that observed in Gba flox/flox ;nestin-Cre mice [5]. Genotyping was performed by polymerase chain reaction (PCR) using genomic DNA extracted from mouse tails.…”

“…The most consistent neuropathological finding reported in human nGD patients is accumulation of lipid-laden macrophages as well as neuronal loss and neuroinflammation [3]. The use of mouse models of nGD [4][5][6] has resulted in the discovery of additional pathways involved in neuropathology, such as neuronal loss [7], neuroinflammation [8] and activation of specific signaling pathways [9,10]. The Gba flox/flox ; nestin-Cre mice [4], a commonly used nGD mouse model, exhibits rapid motor dysfunction associated with severe neuroinflammation and neuronal loss starting at 14 days of age, and develops paralysis by 21 days.…”

“…(b) Mice with a mixed genetic background (C57BL6/J and CBA with further back-crossings with C57BL6/J; Jackson Laboratories, Sacramento, CA, USA), which express Thy1-YFP-H in specific subsets of neurons, including pyramidal neurons of cortical layer V [12]. CBE has been used to induce GD in various mouse strains [13], and the pathology is remarkably similar to that observed in Gba flox/flox ;nestin-Cre mice [5]. CBE has been used to induce GD in various mouse strains [13], and the pathology is remarkably similar to that observed in Gba flox/flox ;nestin-Cre mice [5].…”

The role of glucocerebrosidase in Parkinson disease pathogenesis

“…Neuroinflammation signalling pathways are increasingly being associated with PD pathogenesis . Animals in which the GCase gene is KO or mice were treated with CBE show considerable neuroinflammation, and in particular activation of microglia . This is thought to be due to the accumulation of substrate in the neurons, which can then activate microglia .…”

In vivo inactivation of glycosidases by conduritol B epoxide and cyclophellitol as revealed by activity‐based protein profiling

“…The crystal structure of GBA with bound CBE confirmed the covalent linkage of the compound to the catalytic nucleophile Glu340 . Building on the initial work by Kanfer and coworkers, a regimen using different doses of CBE has been established to generate a phenotypic copy of neuronopathic GD in mice . This pharmacological model is now widely used to study the nature of neuropathology resulting from GBA deficiency, including Parkinsonism .…”