Serum N-glycoproteomics characterization of differential N-glycosylation in schizophrenia

Glycosylation plays a crucial role in neurotransmission and signaling in schizophrenia; however, comprehensive characterization at the glycoproteome level is still lacking. Here we report our site- and structure-specific quantitative N-glycoproteomics characterization of differential N-glycosylation in the sera of schizophrenia patients at the molecular level of intact N-glycopeptide, where comprehensive qualitative (N-glycosite, monosaccharide composition and sequence structures of N-glycans) and quantitative (fold change) information are obtained. With tandem mass tag labeling, liquid chromatography tandem mass spectrometry analysis and site- and structure-specific DB search using GPSeeker, 7855 intact N-glycopeptides were identified corresponding to 1914 peptide backbones, 1997 N-glycosites and 1671 N-glycoprotein; where 1088 intact N-glycopeptides were differentially expressed in the sera of schizophrenia patients (relative to healthy control) with fold change of no less than 1.5. Function annotation of the corresponding N-glycoproteins was carried out. Neurodegeneration and complement pathway were enriched. These findings provide a comprehensive site- and structure-specific picture of aberrant N-glycosylation in schizophrenia and may foster further function and mechanism studies. SIGNIFICANCE: Schizophrenia, as a complex mental disorder, is affecting an increasing number of individuals globally, yet clinical research has struggled to clearly elucidate its pathogenesis. Current diagnostic and treatment approaches largely depend on patient symptoms and behavior, which lack precision. N-glycoproteomics offers a new dimension of understanding by exploring how schizophrenia alters protein glycosylation patterns in the body. Investigating N-glycoproteins not only contributes to the identification of novel early diagnostic biomarkers but also enhances our knowledge of disease pathogenesis. These molecular insights could pave the way for more accurate diagnostic tools and targeted therapies.