S. RAMBOZ, A. PENNINGTON, K. COX, M. HALL, W. ARIAS, K. KAYSER, J. GUTERL, M. BANSAL, D. HAVAS, K. CIRILLO


Parkinson’s disease (PD) and synucleinophathies are neurodegenerative disorders defined by α-synuclein (α-syn) accumulation. Mutations in the α-syn gene have been demonstrated in vitro and in vivo to accelerate the aggregation and formation of α-syn fibrils, a disease marker. Presence of α-syn positive Lewy bodies were identified in neuropathological analyses of a group of Gaucher disease type I [GD] patients [Sidransky, 2005]. Further human genetic studies have also linked glucocerebrosidase (GCase) gene GBA1 mutations to PD making
this mutation the highest genetic risk factor to PD [Sidransky, 2009]. Due to the strong Robust chemically induced animal model of Gaucher disease for preclinical study clinical correlation between PD and GD diseases, animal models that demonstrate relevant and robust phenotypes [behavior, mRNA and protein profiling, IHC, ⋯] are of necessity. Genetically modified animals models carrying point mutations in GCase mimicking type 2 and type 3 have been generated targeting neuronal cells [Enquist et al. 2007; Liu et al. 1998]. In the present study, we focus on a chemically induced model consisting in daily injection of the irreversible GCase inhibitor conduritol B-epoxide (CBE) [Vardi et al., 2016). C57Bl6 mice were dosed daily via intraperitoneal injection at two different doses starting at post-natal day 8 to 22. Each pup was monitored closely and assess to motor, coordination and gait functions weekly from 3 weeks of age until study completion. Gait measures were assessed using PsychoGenics proprietary high through put gait platform, NeuroCube®. Preliminary assessment of data demonstrate progressive and CBE dose-dependent phenotypic deterioration of responses during assessments. Thus, our data demonstrate the progressive and robust phenotype of the chemically-induced GD model as an alternative to genetically modified animal models.