Nuclear-Metabolic Interplay in Down syndrome

Abstract Down syndrome (DS) is a complex genetic disorder with significant physical, cognitive, and behavioral manifestations. Individuals with DS are also more likely to develop certain health conditions including those related to dysfunctional metabolism, such as obesity and diabetes. Further, converging lines of evidence suggest that cellular metabolism is a critical regulator of neurodevelopment, and that metabolites play key roles in regulating neural progenitor cell (NPC) proliferation fate specification required for proper brain development. Despite this, studies have largely overlooked the influence of cellular metabolism on the neurodevelopmental deficits that contribute to DS pathophysiology. This study aims to comprehensively investigate the intricate nuclear-metabolic interplay in DS. Our multifaceted approach utilizing human stem cell and mouse models will decode the molecular, cellular, and tissue level role of cellular metabolism on the brain etiologies observed in DS. We aim to characterize and modulate the nuclear-metabolic axis at three levels during neurodevelopment: 1) glycolysis, 2) lipid/cholesterol metabolism, and 3) histone acetylation. Findings from this study will provide critical insights into the mechanisms underlying aberrant brain development in DS and will uncover promising therapeutic strategies to ameliorate the impact of dysfunctional neurogenesis. Further, our work will shed light on the broader understanding of the nuclear-metabolic interplay during fate specification, differentiation, proliferation and brain morphogenesis. Ultimately, this research will provide the blueprint for exploring the role of the nuclear-metabolic axis broadly in neurodevelopmental disorders, beyond DS, and provide unexplored therapeutic avenues to improve the lives of individuals living with this disorder.