Yael Pewzner-Jung

Weizmann Institute of Science, Israel

A novel chronic neuronopathic Gaucher disease mouse model – approaching the human disease?

We recently generated a novel mouse model that phenocopies aspects of chronic neuronopathic type 3 Gaucher disease (GD). Gba-/-;Gbatg mice harbor a Gba transgene that can be downregulated by doxycycline on a background of Gba knockout mice, enabling their survival. Titration of transgene expression allowed moderate accumulation of the offending substrates, glucosylceramide and glucosylsphingosine. As a result, Gba-/-;Gbatg mice survived for up to 10 months, i.e. significantly longer than mice which model type 2 GD. At around 4 months of age, Gba-/-;Gbatg mice displayed behavioral abnormalities, which deteriorated with age and were associated with significant neuropathology. Moreover, Gba-/-;Gbatg mice exhibited bone deformities, similar to the abnormalities found in type 3 GD patients. I will discuss strengths and weaknesses of the current chronic and acute neuronopathic GD mouse models highlighting their value to shed light on the distinct disease course of type 2 and 3 GD patients.

©2020 by Sphingolipid Biology: Sphingolipids in Physiology and Pathology