{"database":"iProX","file_versions":[],"scores":null,"additional":{"omics_type":["Proteomics"],"submitter":["Qifei Cong"],"species":["Homo Sapiens"],"full_dataset_link":["http://www.iprox.org/page/project.html?id=IPX0016379000"],"submitter_email":["qfcong@suda.edu.cn"],"submitter_affiliation":["Soochow University"],"sample_protocol":[""],"repository":["iProX"],"data_protocol":[""],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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<sup>-/-</sup> and C3aR<sup>-/-</sup> mice and in microglial cultures.<h4>Findings</h4>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<sup>-/-</sup> and C3aR<sup>-/-</sup> mice. Single-cell RNA sequencing and in vitro phagocytosis assay confirmed that BoNT/A modulated phagocytosis-related microglial subclusters.<h4>Interpretation</h4>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.<h4>Funding</h4>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."],"pubmed_title":["The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention."],"pubmed_authors":["Yin Qiao Q, Ding Mengyang M, Tang Yurui Y, Qi Yuwan Y, Qin Yuan Y, Jin Hong H, Li Yang Y, Bao Jili J, Ma Shuyang S, Li Ying Y, Ding Haozhe H, An Xinyu X, Qiao Enyou E, Tang Yan Y, Zhang Qilin Q, Wang Linna L, Shao Jianfeng J, Feng Jianfeng J, Hu Li-Fang LF, Wang Jing J, Fang Pan P, Luo Weifeng W, Cong Qifei Q"],"additional_accession":[]},"is_claimable":false,"name":"Sex-specific proteomic profiles and complement-C3-microglial axis drive depressive symptoms in Parkinson’s disease","description":"In this study, hippocampal and cortical tissues were collected from mice and divided into four experimental groups: control (Con), traumatic brain injury (TBI), control with hydrogen sulfide treatment (Con + H₂S), and TBI with hydrogen sulfide treatment (TBI + H₂S). Each group included three biological replicates, resulting in a total of 24 raw mass spectrometry samples for glycoproteomics analysis.","dates":{"publication":"Thu Apr 02 00:00:00 GMT+01:00 2026"},"accession":"PXD076542","cross_references":{"TAXONOMY":["9606"],"pubmed":["42263400"]}}