Genetic regulators of neuronal survival across metabolic environments

Cellular energy metabolism and oxygen availability shape neuronal function and vulnerability, yet the genetic regulators of these metabolic processes in human neurons remain incompletely understood. Here, we performed CRISPR interference (CRISPRi) screens in human induced pluripotent stem cell (iPSC)-derived neurons across four distinct metabolic conditions and at three physiologically relevant oxygen tensions. This combinatorial approach enabled systematic interrogation of gene-environment interactions that govern neuronal metabolic adaptation. We identified genes-including genes associated with Leigh syndrome and autism spectrum disorder-whose importance for cell survival is highly sensitive to environmental context, revealing potential mechanisms underlying metabolic specification and selective neuronal vulnerability in neurological disorders. Our screens also uncovered regulators of neuronal glycolysis, including <i>KIAA1429</i> and <i>MAPT</i> among others, which are previously uncharacterized modulators of neuronal glucose utilization and metabolic flexibility. Our work nominates candidate metabolic interventions and gene targets for enhancing neuronal resilience under hypoxic or nutrient-limited conditions.