Differential protein network and biological functions atlas from multi-tissue proteomics in patients with depression

Depression leads to complex changes in protein regulation in the brain and other tissues. Reproducibility and data integration remain challenges in this field. We systematically integrated proteomic data from our previous established database Pro-MENDA, encompassing brain, cerebrospinal fluid (CSF), blood, and urine samples from patients with depression. Using a vote-counting statistics to assess consistency of protein expression changes across studies, we identified 2094 different expression proteins from 1804 samples. Functional characterization included Gene Ontology, KEGG pathway enrichment, protein-protein interaction analysis, and post-translational modification. In brain, we observed changes in proteins related to synaptic function and energy metabolism, such as Glial fibrillary acidic protein (GFAP) and Histidine triad nucleotide-binding protein 1 (HINT1). These changes suggest issues with oxidative phosphorylation and synaptic activity. The CSF and blood revealed immune-inflammatory markers like Afamin (AFM) and Serpin Family F Member 1 (SERPINF1), while urine analysis showed signs of neutrophil activation. We also identified 13 shared proteins across brain, CSF, and blood, including Clusterin (CLU), that link complement and coagulation, and reactive oxygen pathways. In this protein-protein interaction network of brain, proteins related to cell adhesion, respiration, neuron and synapse are significantly enriched. Post-translational modifications, particularly phosphorylation, were common. Our findings highlight systemic protein dysregulation in depression. This connects brain and peripheral mechanisms, offering insights for identifying multi-tissue biomarkers and developing targeted therapies.