A new mouse model exploring chronic neuronopathic Gaucher Disease

Gaucher disease (GD) is an inherited metabolic disease resulting from mutations in the GBA1 gene coding for lysosomal glucocerebrosidase (GC). GD can be divided into neurological (Type 2 and 3 GD) and non-neurological forms (Type 1 GD). Since enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) cannot cross the blood brain barrier, no therapy is currently available for neuronopathic forms of GD. In addition, ERT and SRT have limited efficacy for bone pathology, found in Type 3 and Type 1 GD patients. Mouse models for neuronopathic GD are currently available for type 2 GD and the animals display a short life span of 3 weeks. Chronic type 3 GD currently lacks a good pre-clinical system. Here we report the generation of a new mouse model that is based on a tet-off inducible GBA1 transgene crossed on a Gba1 null background (GBA-/-:Gba^tg mice). When doxycycline is given to Gba-/-:Gba^tg mice ~2 months of age, GC levels are reduced by ~70%. Mice develop a chronic form of GD by 7-9 months and display massive gliosis in defined brain areas. In the cerebellum, gliosis was accompanied with loss of Purkinje neurons similar to what is found in type 3 GD patients. In addition, mice develop bone deformations and exhibit severe kyphosis as in type 3 GD patients. We are interested to know what the molecular mechanisms are that lead to the CNS and bone pathology and to compare them with GD human pathology as well as with the acute GD mouse model.