Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation
Abstract The switch from oxidative phosphorylation to glycolysis is crucial for microglial activation. Recent studies highlight that histone lactylation promotes macrophage homeostatic gene expression via transcriptional regulation, but its role in microglia activation in Parkinson’s disease (PD) re...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00858-0 |
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| author | Qixiong Qin Danlei Wang Yi Qu Jiangting Li Ke An Zhijuan Mao Jingyi Li Yongjie Xiong Zhe Min Zheng Xue |
| author_facet | Qixiong Qin Danlei Wang Yi Qu Jiangting Li Ke An Zhijuan Mao Jingyi Li Yongjie Xiong Zhe Min Zheng Xue |
| author_sort | Qixiong Qin |
| collection | DOAJ |
| description | Abstract The switch from oxidative phosphorylation to glycolysis is crucial for microglial activation. Recent studies highlight that histone lactylation promotes macrophage homeostatic gene expression via transcriptional regulation, but its role in microglia activation in Parkinson’s disease (PD) remains unclear. Here, we demonstrated that inhibiting glycolysis with 2-deoxy-d-glucose alleviates microgliosis, neuroinflammation and dopaminergic neurons damage by reducing lactate accumulation in PD mice. Notably, we observed a marked increase in histone lactylation, particularly H3K9 lactylation, in microglia in the substantia nigra of PD mice. Mechanistically, CUT&Tag and Chip-qPCR analyses revealed that H3K9 lactylation enriched at the SLC7A11promoter and activated its expression. Importantly, inhibiting SLC7A11 by sulfasalazine mitigated microglia-mediated neuroinflammation and improved motor function in PD mice. Moreover, we found that lactate-induce histone lactylation is dependent on P300/CBP. Collectively, our findings demonstrate that glycolysis-derived lactate promotes microglial activation via histone lactylation and provide a potential therapeutic strategy for PD. |
| format | Article |
| id | doaj-art-20522d9d5bb4440bb8ae4c56a706b559 |
| institution | DOAJ |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-20522d9d5bb4440bb8ae4c56a706b5592025-08-20T02:53:47ZengNature Portfolionpj Parkinson's Disease2373-80572025-01-0111111510.1038/s41531-024-00858-0Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylationQixiong Qin0Danlei Wang1Yi Qu2Jiangting Li3Ke An4Zhijuan Mao5Jingyi Li6Yongjie Xiong7Zhe Min8Zheng Xue9Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract The switch from oxidative phosphorylation to glycolysis is crucial for microglial activation. Recent studies highlight that histone lactylation promotes macrophage homeostatic gene expression via transcriptional regulation, but its role in microglia activation in Parkinson’s disease (PD) remains unclear. Here, we demonstrated that inhibiting glycolysis with 2-deoxy-d-glucose alleviates microgliosis, neuroinflammation and dopaminergic neurons damage by reducing lactate accumulation in PD mice. Notably, we observed a marked increase in histone lactylation, particularly H3K9 lactylation, in microglia in the substantia nigra of PD mice. Mechanistically, CUT&Tag and Chip-qPCR analyses revealed that H3K9 lactylation enriched at the SLC7A11promoter and activated its expression. Importantly, inhibiting SLC7A11 by sulfasalazine mitigated microglia-mediated neuroinflammation and improved motor function in PD mice. Moreover, we found that lactate-induce histone lactylation is dependent on P300/CBP. Collectively, our findings demonstrate that glycolysis-derived lactate promotes microglial activation via histone lactylation and provide a potential therapeutic strategy for PD.https://doi.org/10.1038/s41531-024-00858-0 |
| spellingShingle | Qixiong Qin Danlei Wang Yi Qu Jiangting Li Ke An Zhijuan Mao Jingyi Li Yongjie Xiong Zhe Min Zheng Xue Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation npj Parkinson's Disease |
| title | Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation |
| title_full | Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation |
| title_fullStr | Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation |
| title_full_unstemmed | Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation |
| title_short | Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation |
| title_sort | enhanced glycolysis derived lactate promotes microglial activation in parkinson s disease via histone lactylation |
| url | https://doi.org/10.1038/s41531-024-00858-0 |
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