Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease
Abstract Microglia-mediated neuroinflammation plays a crucial role in the progression of Parkinson’s disease (PD). Dysregulation of lipid droplet homeostasis is a significant factor affecting microglial inflammatory responses, but the mechanisms underlying lipid droplet imbalance in PD are currently...
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| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03517-0 |
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| author | Chunlei Han Huizhi Wang Moxuan Zhang Liuliu Wu Anni Wang Pengda Yang Yuan Gao Chaonan Zhang Jianing Gao Tao Xue Tingting Du Yucheng Ji Lin Shi Chunkui Zhang Renpeng Li Yilei Xiao Jianguo Zhang Fangang Meng |
| author_facet | Chunlei Han Huizhi Wang Moxuan Zhang Liuliu Wu Anni Wang Pengda Yang Yuan Gao Chaonan Zhang Jianing Gao Tao Xue Tingting Du Yucheng Ji Lin Shi Chunkui Zhang Renpeng Li Yilei Xiao Jianguo Zhang Fangang Meng |
| author_sort | Chunlei Han |
| collection | DOAJ |
| description | Abstract Microglia-mediated neuroinflammation plays a crucial role in the progression of Parkinson’s disease (PD). Dysregulation of lipid droplet homeostasis is a significant factor affecting microglial inflammatory responses, but the mechanisms underlying lipid droplet imbalance in PD are currently unclear. Here, we report a subtype of microglia characterized by high expression of long-chain acyl-CoA synthetase 1 (ACSL1) through single-nucleus RNA sequencing analysis and machine learning algorithms, linking lipid metabolism to PD neuroinflammation. The results of multiple loss- and gain-of-function experiments indicate that ACSL1 localized to the endoplasmic reticulum (ER) promotes lipid droplet accumulation to exacerbate microglial activation and dopaminergic neurons death. Mechanistically, activation of TANK-binding kinase 1 (TBK1) leads to the enrichment of ACSL1 on the endoplasmic reticulum, which generates acyl-CoA that are channelled for lipid droplet biogenesis. Additionally, high expression of ACSL1 promotes activation of TBK1 through Nrdp1-mediated K63 ubiquitination of TBK1, which triggers the amplification of the aforementioned biological effects. Moreover, NF-κB directly binds to the ACSL1 promoter and positively regulates its transcription, resulting in increased ACSL1 expression in microglia. Our findings suggest that manipulating lipid droplet biogenesis by modulating ACSL1 may be a potential strategy for treating neuroinflammation in PD patients. |
| format | Article |
| id | doaj-art-04caaaa19fec4fd391e617a6ab1ccf19 |
| institution | DOAJ |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-04caaaa19fec4fd391e617a6ab1ccf192025-08-20T03:05:16ZengBMCJournal of Neuroinflammation1742-20942025-07-0122112710.1186/s12974-025-03517-0Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s diseaseChunlei Han0Huizhi Wang1Moxuan Zhang2Liuliu Wu3Anni Wang4Pengda Yang5Yuan Gao6Chaonan Zhang7Jianing Gao8Tao Xue9Tingting Du10Yucheng Ji11Lin Shi12Chunkui Zhang13Renpeng Li14Yilei Xiao15Jianguo Zhang16Fangang Meng17Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityResearch Center of Clinical Epidemiology, Peking University Third HospitalDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityCenter of Cognition and Brain Science, Beijing Institute of Basic Medical SciencesDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Liaocheng People’s HospitalDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityAbstract Microglia-mediated neuroinflammation plays a crucial role in the progression of Parkinson’s disease (PD). Dysregulation of lipid droplet homeostasis is a significant factor affecting microglial inflammatory responses, but the mechanisms underlying lipid droplet imbalance in PD are currently unclear. Here, we report a subtype of microglia characterized by high expression of long-chain acyl-CoA synthetase 1 (ACSL1) through single-nucleus RNA sequencing analysis and machine learning algorithms, linking lipid metabolism to PD neuroinflammation. The results of multiple loss- and gain-of-function experiments indicate that ACSL1 localized to the endoplasmic reticulum (ER) promotes lipid droplet accumulation to exacerbate microglial activation and dopaminergic neurons death. Mechanistically, activation of TANK-binding kinase 1 (TBK1) leads to the enrichment of ACSL1 on the endoplasmic reticulum, which generates acyl-CoA that are channelled for lipid droplet biogenesis. Additionally, high expression of ACSL1 promotes activation of TBK1 through Nrdp1-mediated K63 ubiquitination of TBK1, which triggers the amplification of the aforementioned biological effects. Moreover, NF-κB directly binds to the ACSL1 promoter and positively regulates its transcription, resulting in increased ACSL1 expression in microglia. Our findings suggest that manipulating lipid droplet biogenesis by modulating ACSL1 may be a potential strategy for treating neuroinflammation in PD patients.https://doi.org/10.1186/s12974-025-03517-0ACSL1Parkinson’s diseaseMicrogliaLipid dropletNeuroinflammationTBK1 |
| spellingShingle | Chunlei Han Huizhi Wang Moxuan Zhang Liuliu Wu Anni Wang Pengda Yang Yuan Gao Chaonan Zhang Jianing Gao Tao Xue Tingting Du Yucheng Ji Lin Shi Chunkui Zhang Renpeng Li Yilei Xiao Jianguo Zhang Fangang Meng Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease Journal of Neuroinflammation ACSL1 Parkinson’s disease Microglia Lipid droplet Neuroinflammation TBK1 |
| title | Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease |
| title_full | Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease |
| title_fullStr | Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease |
| title_full_unstemmed | Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease |
| title_short | Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson’s disease |
| title_sort | activated tbk1 promotes acsl1 mediated microglia lipid droplet accumulation and neuroinflammation in parkinson s disease |
| topic | ACSL1 Parkinson’s disease Microglia Lipid droplet Neuroinflammation TBK1 |
| url | https://doi.org/10.1186/s12974-025-03517-0 |
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