| Autor: |
Duffy HBD; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America., Byrnes C; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America., Zhu H; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America., Tuymetova G; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America., Lee YT; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America., Platt FM; Department of Pharmacology, University of Oxford, Oxford, United Kingdom., Proia RL; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States of America. |
| Jazyk: |
angličtina |
| Zdroj: |
JCI insight [JCI Insight] 2024 Sep 17. Date of Electronic Publication: 2024 Sep 17. |
| DOI: |
10.1172/jci.insight.179126 |
| Abstrakt: |
Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, 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 novel, 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 novel 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 novel 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
