The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention.
Overview
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Institute of Molecular Enzymology, School of Life Sciences, Suzhou Medical College, Soochow University, Suzhou, 215123, China
- Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 201203, China
- Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, China
- Department of Neurology, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, 313000, China
- Lanzhou Biotechnique Development Co., Ltd., Lanzhou, Gansu, 730000, China
- Department of Neurology, The Third People's Hospital of Zhangjiagang City, Suzhou, 215600, Jiangsu, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
- Biomedical Basic Research Center (BBRC) of Jiangsu, Soochow University, Suzhou, 215123, China
- Department of Nephrology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Institute of Neurological Diseases, Soochow University-Suzhou Blue Cross Brain Hospital, Soochow University, Suzhou, 215123, China
- School of Life Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, 215123, China
Abstract
Background: Depression is a common and early non-motor symptom of Parkinson's disease (PD) with significant sexual dimorphism, yet its underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the sex-specific plasma proteomic profiles of depression in patients with PD (DPD) and to investigate the role of complement-mediated synaptic pruning in its pathophysiology.
Methods: Plasma proteomic analysis was performed on data from the Parkinson's Progression Markers Initiative (PPMI) and an independent validation cohort, stratified by sex. Functional enrichment analyses identified dysregulated pathways. A chronic MPTP/
Findings: Proteomic profiling revealed both conserved complement-driven immune dysfunction and profound sex-divergent molecular perturbations underlying PD and DPD. Complement and coagulation cascades were consistently upregulated in both sexes. In MPTP-treated male and female mice, hippocampal complement components (C1Q, C3, C3aR) and downstream signalling (p-STAT3, p-P65) were elevated, accompanied by microglial synapse phagocytosis and depressive-like behaviours. Genetic deletion of C3 rescued both MPTP-induced motor and depressive-like behavioural deficits and prevented hippocampal synaptic loss associated with microglial synaptic engulfment. BoNT/
Interpretation: DPD exhibits distinct sex-specific immune signatures, with convergent complement pathway activation driving microglial synaptic pruning and depressive symptoms. The antidepressant effect of BoNT/
Funding: National Natural Science Foundation of China, Key Project of the Natural Science Foundation of Jiangsu Provincial Higher Education Institutions, Project of Biomedical Basic Research Center (BBRC) of Jiangsu, Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow University, Project of MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases; The Lingang Laboratory fund; Shanghai Science and Technology Innovation Sailing Special Project, and Shanghai Municipal Science and Technology Major Project; Zhejiang Provincial Natural Science Foundation of China.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE308594 — at NCBI GEO; found in “Data sharing statement”
Data sharing statement
Single-cell RNA sequencing data have been archived in the Gene Expression Omnibus (GEO) under accession number GEO: GSE308594 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Authors: added Li-Fang Hu (0000-0001-8326-7779); removed Li-Fang Hu
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 23 authors, 6 keywords, 15 MeSH terms, 9 funders, 104 references, 31 RRIDs.
Cite
This paper
Yin, Q., Ding, M., Tang, Y., Qi, Y., Qin, Y., Jin, H., Li, Y., Bao, J., Ma, S., Li, Y., Ding, H., An, X., Qiao, E., Tang, Y., Zhang, Q., Wang, L., Shao, J., Feng, J., Hu, L.-F., . . . Cong, Q. (2026). The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention. EBioMedicine, 129, 106325. https://
BibTeX
@article{yin2026compleme
author = {Yin, Qiao and Ding, Mengyang and Tang, Yurui and Qi, Yuwan and Qin, Yuan and Jin, Hong and Li, Yang and Bao, Jili and Ma, Shuyang and Li, Ying and Ding, Haozhe and An, Xinyu and Qiao, Enyou and Tang, Yan and Zhang, Qilin and Wang, Linna and Shao, Jianfeng and Feng, Jianfeng and Hu, Li-Fang and Wang, Jing and Fang, Pan and Luo, Weifeng and Cong, Qifei},
title = {{The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention}},
journal = {EBioMedicine},
year = {2026},
month = jun,
volume = {129},
pages = {106325},
publisher = {Elsevier},
issn = {2352-3964},
doi = {10.1016/
url = {https://
pmid = {42263400},
pmcid = {PMC13273220}
}
RIS
TY - JOUR
AU - Yin, Qiao
AU - Ding, Mengyang
AU - Tang, Yurui
AU - Qi, Yuwan
AU - Qin, Yuan
AU - Jin, Hong
AU - Li, Yang
AU - Bao, Jili
AU - Ma, Shuyang
AU - Li, Ying
AU - Ding, Haozhe
AU - An, Xinyu
AU - Qiao, Enyou
AU - Tang, Yan
AU - Zhang, Qilin
AU - Wang, Linna
AU - Shao, Jianfeng
AU - Feng, Jianfeng
AU - Hu, Li-Fang
AU - Wang, Jing
AU - Fang, Pan
AU - Luo, Weifeng
AU - Cong, Qifei
TI - The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention
T2 - EBioMedicine
J2 - eBioMedicine
PY - 2026
DA - 2026/
VL - 129
SP - 106325
SN - 2352-3964
PB - Elsevier
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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