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

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

  • Neurobiol Dis. 2025 Jun 1:209:106899. doi: 10.1016/j.nbd.2025.106899.
Shuxia Wen 1,  Yajun Li 2,  Wanqing Xiang 1,  Fei Shen 1,  Nan Jiang 1,  Duan Ma 3,  Jin Zhang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200032 Shanghai, China.
  • 2 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200032 Shanghai, China; Huashan Hospital, Fudan University, 200040 Shanghai, China.
  • 3 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200032 Shanghai, China; Surgery laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China; Children's Hospital, Fudan University, 201102 Shanghai, China; Institute of medical genetics and genomics, Fudan University, 201102 Shanghai, China. Electronic address: duanma@fudan.edu.cn.
  • 4 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200032 Shanghai, China; Surgery laboratory, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China. Electronic address: jinzhang@fudan.edu.cn.
PMID: 40194636 DOI: 10.1016/j.nbd.2025.106899
Abstract

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.

Keywords

Gba1, chronic neuronopathic Gaucher disease; Mouse model.

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