Gaucher’s disease is a glycosphingolipid-storage disease in which homozygous mutations are found in the lysosomal enzyme glucocerebrosidase (GBA) gene. PD and Gaucher’s disease share many clinical and neuropathological features. Dr. LoBianco will clarify the role of the GBA gene in PD by generating and characterizing a mouse that lacks the GBA gene specifically in dopaminergic neurons. These conditional knockout mice will be tested for motor deficits, dopaminergic cell loss, and the presence of proteinaceous inclusions in dopaminergic neurons. The novel animal model may eventually be used to develop predictive therapeutic inclusions.
Final Outcome
As mutations in the glucocerebrosidase (GBA) gene are considered to be a risk factor for sporadic Parkinson's disease, we developed a mutant preclinical model with a selective disruption of the GBA gene in midbrain dopamine neurons. As far as one year of age, the majority of mutant models did not display any behavioral impairment or dopaminergic neurodegeneration. Only very few models demonstrated a clear and selective degeneration of the nigrostriatal pathway. Puzzling!
We received supplemental funding to answer the next obvious question: how to increase the number of affected models in order to develop a relevant and useful model of sporadic PD for testing novel neuroprotective therapies.