The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention
eBioMedicine, 2026
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., Wang J., Fang P., Luo W., Cong Q.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology | Plasma |  Olink Explore 3072/384 |
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/probenecid-induced mouse model of PD was used to validate findings. Behavioural tests assessed motor and depressive-like phenotypes. Proteomic, biochemical, and imaging techniques were used to evaluate protein expression, synapse density, and microglial phagocytosis. The therapeutic mechanism of Botulinum Neurotoxin A (BoNT/A) on DPD was investigated in wild-type, C3−/− and C3aR−/− mice and in microglial cultures.
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/A treatment alleviated depressive-like behaviours and reduced microglial synaptic engulfment in an MPTP model; these therapeutic effects were abolished in C3−/− and C3aR−/− mice. Single-cell RNA sequencing and in vitro phagocytosis assay confirmed that BoNT/A modulated phagocytosis-related microglial subclusters.
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/A is mediated through inhibition of the C3–C3aR signalling axis. These findings highlight the potential for sex-stratified diagnostics and complement-targeted therapies for depression in patients with PD. A key limitation is that our clinical analyses were constrained by limited validation cohort sizes, and mechanistic studies were limited to male mice, which may restrict the generalisability of our findings to female populations.