Integrative Analysis of Proteomics and Metabolomics Reveals Impacts of Sam2 Knockout on Autism Spectrum Disorders

Abstract

Neurokine Sam2 deficiency is associated with behavioral abnormalities including heightened anxiety and fear responses across evolutionarily conserved model organisms. Here, we employed an integrated proteomics and metabolomics approach using liquid chromatography-mass spectrometry (LC-MS) to elucidate molecular signatures associated with autism spectrum disorder (ASD) in Sam2 knockout mice. Comparative analysis of blood plasma samples from Sam2 knockout and wild-type mice revealed substantial alterations in both proteomic and metabolomic profiles. Proteomic analysis identified 68 differentially expressed proteins (comprising 102 peptides), with notable upregulation of complement component C1qc and downregulation of apolipoprotein A1 (Apoa1), implicating dysregulation of complement cascade pathways. Metabolomic profiling uncovered 15 significantly altered metabolites: nine upregulated species including D-glucuronic acid and 5,10-Methylenetetrahydrofolate, and six downregulated metabolites including folinic acid and acetate. Integrative pathway analysis revealed perturbations in glycolysis/gluconeogenesis and glycerophospholipid metabolism, providing mechanistic insights into the molecular consequences of Sam2 deficiency. These findings identify potential biomarkers for anxiety-related disorders and ASD while advancing our understanding of the complex interplay between genetic alterations and proteomic-metabolomic networks in neurodevelopmental conditions. Our results establish a foundation for developing targeted therapeutic interventions and highlight the utility of multi-omics approaches in dissecting the molecular basis of behavioral disorders.