Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model
Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, which is responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosis, astrogliosis, and neurodegeneration. However, the role that microglia, astrocytes, and neurons play in the disease remains to be determined. In the current study, we developed inducible, cell-type specific Gba KO mice to understand the individual impacts of Gba deficiencies on microglia and neurons. Gba was conditionally knocked out either exclusively in microglia or neurons, or throughout the body. These mouse models were developed using a tamoxifen-inducible Cre system, with tamoxifen administration commencing at weaning. Microglia-specific Gba KO mice showed no signs of disease. However, the neuron-specific Gba KO resulted in a shortened lifespan, severe weight loss, and ataxia. These mice also had significant neurodegeneration, microgliosis, and astrogliosis accompanied by the accumulation of glucosylceramide and glucosylsphingosine, recapitulating Gaucher disease-like symptoms. These surprising findings reveal that, unlike the neuron-specific Gba deficiency, microglia-specific Gba deficiency alone does not induce disease. The neuronal Gaucher disease mouse model, with a median survival of 16 weeks, may be useful for future studies of pathogenesis and the evaluation of therapies. Overall design: In order to explore mechanisms of Gba deficiencies, cell-specific (microglial and neuronal) Gba KO mice were developed. We then performed bulk RNAseq from brain tissue. Each group (neuron-specific Gba KO (Gba nKO), microglia-specific Gba KO (Gba mKO), Gba nKO littermate controls, Gba mKO littermate controls) consisted of 6 samples. CD11b+ cells were also isolated from 4 Gba mKO (Gba mmKO) and 4 control mice for bulk RNAseq.