Brain pathology and cerebellar purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease

Abstract

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^-/-;Gba^tg 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^-/-;Gba^tg 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^-/-;Gba^tg mice being a genuine type 3 GD model. Together, the Gba^-/-;Gba^tg 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.

Keywords: Acid-beta glucosidase; Cerebellum; Gaucher disease (GD); Gba(-/-);Gba(tg) mice; Neuropathology; Parkinson's disease; Purkinje neurons; Sphingolipids.