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

This is the authors' abstract. We don't add key points for this paper.

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 Gba1 flox/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. • A chronic neuronopathic Gaucher disease (GD) model was created using Gba1 flox/F213I ; UBC-CreERT2 mice, showing prolonged lifespan, splenomegaly, Gaucher-like cell infiltration, and reduced GCase activity. • The model exhibited chronic neuroinflammation and later developed Parkinson’s disease (PD)-like features, including loss of TH-positive neurons in the substantia nigra. • Elevated α-synuclein expression was also observed, linking GD to PD-like neurodegeneration.