| First Author | Shimizu T | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 2 | Pages | 307-319.e8 |
| PubMed ID | 36736320 | Mgi Jnum | J:336297 |
| Mgi Id | MGI:7437262 | Doi | 10.1016/j.immuni.2023.01.008 |
| Citation | Shimizu T, et al. (2023) Direct activation of microglia by beta-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease. Immunity 56(2):307-319.e8 |
| abstractText | Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of beta-glucosylceramide (beta-GlcCer). However, it remains unclear how beta-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that beta-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD. |
