A novel mouse model of chronic neuronopathic Gaucher disease exhibits Parkinson's disease-like phenotypes.

Gaucher disease (GD), the most common lysosomal storage disorder, is an autosomal recessive inherited disease caused by mutations in GBA1. It can be categorized into neuronopathic and non-neuronopathic types. We previously constructed mouse models carrying the Gba1 F213I point mutation and tamoxifen-inducible systemic Gba1 knockout mice, both of which developed disease rapidly and had a short lifespan. This study combined these two models to create Gba1flox/F213I; UBC-CreERT2 mice. These mice exhibited a significantly extended lifespan, along with splenomegaly, infiltration of Gaucher-like cells, and reduced β-glucocerebrosidase (GCase) activity. Additionally, they displayed chronic neuroinflammation. In the later stages, these mice also exhibited typical pathological features of Parkinson's disease (PD), including a reduction in dopaminergic neurons in the substantia nigra pars compacta (SNpc) and an increase in the expression levels of the α-synuclein (α-syn) protein. RNA sequencing (RNA-seq) from the brain tissues of these mice revealed an early, robust inflammatory response, particularly with the activation of the interferon pathway, including the downstream expression of MHC I complex molecule genes, which was confirmed through Western blot analysis. In summary, we established a chronic neurogenic Gaucher disease mouse model that exhibited pronounced inflammatory activation and developed Parkinsonian-like phenotypes in the later stages.