Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression
Abstract Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSY...
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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/s41531-024-00846-4 |
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| author | Zhen Zhang Kun Niu Taoying Huang Jiali Guo Gongbikai Xarbat Xiaoli Gong Yunke Gao Feiyang Liu Shan Cheng Wenting Su Fei Yang Zhaoyuan Liu Florent Ginhoux Ting Zhang |
| author_facet | Zhen Zhang Kun Niu Taoying Huang Jiali Guo Gongbikai Xarbat Xiaoli Gong Yunke Gao Feiyang Liu Shan Cheng Wenting Su Fei Yang Zhaoyuan Liu Florent Ginhoux Ting Zhang |
| author_sort | Zhen Zhang |
| collection | DOAJ |
| description | Abstract Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice, which were further validated on protein level. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult. |
| format | Article |
| id | doaj-art-222e1c54b30746d2b58c3a500f0b8806 |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-222e1c54b30746d2b58c3a500f0b88062025-01-12T12:12:39ZengNature Portfolionpj Parkinson's Disease2373-80572025-01-0111111610.1038/s41531-024-00846-4Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpressionZhen Zhang0Kun Niu1Taoying Huang2Jiali Guo3Gongbikai Xarbat4Xiaoli Gong5Yunke Gao6Feiyang Liu7Shan Cheng8Wenting Su9Fei Yang10Zhaoyuan Liu11Florent Ginhoux12Ting Zhang13Department of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Physiology and Pathophysiology, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityDepartment of Medical Genetics and Developmental Biology, Capital Medical UniversityBeijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical UniversityDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineDepartment of Neurobiology, Center of Parkinson Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory on Parkinson Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical UniversityAbstract Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice, which were further validated on protein level. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult.https://doi.org/10.1038/s41531-024-00846-4 |
| spellingShingle | Zhen Zhang Kun Niu Taoying Huang Jiali Guo Gongbikai Xarbat Xiaoli Gong Yunke Gao Feiyang Liu Shan Cheng Wenting Su Fei Yang Zhaoyuan Liu Florent Ginhoux Ting Zhang Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression npj Parkinson's Disease |
| title | Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression |
| title_full | Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression |
| title_fullStr | Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression |
| title_full_unstemmed | Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression |
| title_short | Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson’s disease model triggered by α-synuclein overexpression |
| title_sort | microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse parkinson s disease model triggered by α synuclein overexpression |
| url | https://doi.org/10.1038/s41531-024-00846-4 |
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