Brain subcellular proteomics reveals chromosome segregation as a potentially key molecular pathway in Down syndrome

Down syndrome (DS), caused by trisomy of chromosome 21, remains incompletely understood at the molecular level, particularly with respect to alterations in subcellular protein distribution in the brain. In this study, we performed a systematic proteomic analysis of DS brain tissue to investigate changes in nuclear-to-cytoplasmic (N/C) protein abundance ratios. As a result, we identified 150 proteins exhibiting significant alterations in nucleocytoplasmic distribution in DS brain tissue, as defined by differential N/C ratios relative to normal controls. Among these proteins, SGO2 and TOP2A displayed markedly reduced nuclear relative abundance, reflected by decreased N/C ratios. Functional enrichment analysis revealed that proteins with altered nucleocytoplasmic distribution were associated with biological processes related to cell cycle regulation, including sister chromatid segregation, as well as pathways involved in RNA metabolism, oxidative stress responses, lipid metabolism, and immune regulation. These findings suggest that altered nucleocytoplasmic protein distribution may be associated with disturbances in multiple cellular processes relevant to DS pathology. Network analysis further identified SGO2 as a central hub protein among proteins exhibiting altered nucleocytoplasmic distribution. Given its established role in chromosome cohesion, reduced nuclear relative abundance of SGO2 may be associated with dysregulation of chromosome segregation and increased susceptibility to genome instability in DS brain tissue. Overall, this study provides a systems-level characterization of altered nucleocytoplasmic protein distribution in DS brain tissue and highlights molecular pathways potentially affected by these changes. Our findings offer a resource of candidate proteins and pathways for future mechanistic and functional studies aimed at elucidating how altered protein spatial organization contributes to DS pathogenesis.