Brain pathology and cerebellar Purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease [whole brain]

Gaucher disease (GD) is currently the focus of considerable attention due primarily to the association between the gene that causes GD (GBA) and Parkinson’s disease. Mouse models exist for the systemic (type 1) and for the acute neuronopathic forms (type 2) of GD. Here we report the generation of a mouse that phenotypically models chronic neuronopathic type 3 GD. Gba-/-;Gbatg mice, which contain a Gba transgene regulated by doxycycline, accumulate moderate levels of the offending substrate in GD, glucosylceramide, and live for up to 10 months, i.e. significantly longer than mice which model type 2 GD. Gba-/-;Gbatg mice display behavioral abnormalities at ~4 months, which deteriorate with age, along with significant neuropathology including loss of Purkinje neurons. Gene expression is altered in the brain and in isolated microglia, although the changes in gene expression are less extensive than in mice modeling type 2 disease. Finally, bone deformities are consistent with the Gba-/-;Gbatg mice being a genuine type 3 GD model. Together, the Gba-/-;Gbatg mice share pathological pathways with acute neuronopathic GD mice but also display differences that might help understand the distinct disease course and progression of type 2 and 3 patients. RNA was isolated from whole brain homogenates of C57BL/6 6-9 months old Gba-/-;GbaTg Chronic Gaucher disease mouse model and littermate control Gba+/-;GbaTg and Gba+/+ mice after administration of doxycycline for ~4-7 months. In addition, RNA was isolated from whole brain homogenates of C57BL/6 wildtype mice, injected with conduritol B-epoxide (CBE) from P8-P21 to induce acute Gaucher disease, or control mice injected in parallel with PBS were examined on P21.