These Gba*R463C mice contain the mutation R463C in intron 10 of the glucosidase, beta, acid (Gba) gene. This mutation introduces an arginine to cysteine mutation analogous to a common Gba mutation found in humans with the α-synucleinopathy Gaucher disease. In Gaucher disease, mutations of the lysosomal enzyme GBA prevents the degradation of its substrate, glucocerebroside, into ceramide and glucose, resulting in an accumulation of glucocerebroside within lysosomes mainly in macrophages. These lipid-filled mutant macrophages contribute to the enlargement of the spleen and liver, damage to blood-forming tissues, bone fractures and pain, and damage to the lungs and nervous tissues. Gaucher disease is rare, but is more prevalent among individuals of Ashkenazi Jewish descent. Carriers of GBA mutations often have a higher genetic risk of developing Parkinson's disease and Lewy body.
Homozygous Gba*R463C mice are viable and fertile. The R463C mutation is associated with less severe type 1 non-neuronopathic Gaucher disease characterized by later onset of major visceral and progressive CNS disease. The Gba enzyme activity in liver and spleen was 35% and 13% of the Gba enzyme activity in normal mice, respectively. Gba activity levels in brain were 65% of wildtype. Enhanced α-syn accumulation and astroglial activation are apparent in the nigrostriatal pathway of these mice. These are relevant for the study of Gaucher and Parkinson's disease.
