Unveiling the Human Plasma Interactome of Neuromelanin: Associations with Inflammation, Vascular Function, and Neurodegeneration Pathways

Background Neuromelanin (NM), a neuronal pigment linked to catecholamine metabolism, has been implicated in both protective and detrimental roles in neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. Given the continuity between plasma and cerebrospinal fluid and the accessibility of plasma as a protein-rich biofluid, we aimed to identify and characterize neuromelanin-binding plasma proteins (NBPPs) to gain insight into peripheral and potentially brain-relevant interactions. Methods NBPPs in pooled plasma were identified by affinity chromatography using two NM analogs (poly-L-DOPA and poly-noradrenaline). Following stringent washing and LC-MS/MS analysis, proteins were evaluated by structural bioinformatics, Gene Ontology, and protein–protein interactome analyses. Data are available at DOI: 10.4321/repisalud.27499. Results We identified 98 NBPPs, 51 (52%) of which bound both NM analogs, suggesting shared physicochemical determinants. NBPPs were more extensively glycosylated than non-NBPPs. Abundant NBPPs were typically larger and displayed increased 3₁₀-helix content, whereas low-abundance NBPPs exhibited reduced α-helix and increased β-sheet content. Functional enrichment analyses associated NBPPs with inflammation, immune regulation, complement activation, vascular biology, and amyloid-related processes. NBPPs included hub proteins such as ApoE and adiponectin, while several served as highly connected network nodes, suggesting indirect links between NM and neuroinflammation or protein aggregation. Conclusions These findings provide a novel perspective on NM involvement in neurodegeneration through interactions with functionally relevant plasma proteins and potentially their CSF or brain counterparts. Although based on plasma, this approach provides a peripheral proxy to explore NM-associated pathways relevant to CNS pathology and may ultimately support NM-centered diagnostic strategies for early-stage disease.