Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson's disease model triggered by α-synuclein overexpression

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

doi:10.1038/s41531-024-00846-4

Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson's disease model triggered by α-synuclein overexpression

NPJ Parkinsons Dis. 2025 Jan 9;11(1):15. doi: 10.1038/s41531-024-00846-4.

Authors

Zhen Zhang¹, Kun Niu¹, Taoying Huang¹, Jiali Guo¹, Gongbikai Xarbat¹, Xiaoli Gong², Yunke Gao¹, Feiyang Liu¹, Shan Cheng³, Wenting Su^{4

5}, Fei Yang¹, Zhaoyuan Liu^{6

7}, Florent Ginhoux^{6

8

9

10

11}, Ting Zhang¹²

Affiliations

¹ Department 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 University, Beijing, 100069, China.
² Department of Physiology and Pathophysiology, Capital Medical University, Beijing, 100069, China.
³ Department of Medical Genetics and Developmental Biology, Capital Medical University, Beijing, 100069, China.
⁴ Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China.
⁵ Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.
⁶ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁷ Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁸ Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Republic of Singapore.
⁹ Gustave Roussy Cancer Campus, Villejuif, 94800, France.
¹⁰ Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale Contre le Cancer, Villejuif, France.
¹¹ Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore.
¹² Department 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 University, Beijing, 100069, China. [email protected].

PMID: 39779738
DOI: 10.1038/s41531-024-00846-4

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.

Abstract

Grants and funding