Neddylation is a post-translational modification in which NEDD8 is conjugated to target proteins to regulate their stability, localization, and activity. This process is initiated by NAE1, an E1 enzyme that catalyzes the first step of the transfer. While neddylation dysregulation has been extensively explored in different cancer types and metabolic diseases, its role in brain aging and age-related neurodegenerative diseases remains poorly understood. To elucidate the impact of neddylation in aging we employ a multimodal approach, integrating young and old NAE1 heterozygous mice, human brain samples, in vitro astrocytic and iPS cells derived neuronal models, direct pharmacological inhibition, in vivo astrocyte specific NAE1 complete deletion and publicly available datasets. Neddylation increased with age in mice and human samples, whereas its disruption in vivo drives cognitive decline and neuroinflammatory activation. Pharmacological inhibition of neddylation in astrocytes drives a senescence-associated, pro-inflammatory secretory state that disrupts neuronal activity in a non–cell-autonomous manner. Overall, our findings suggest that neddylation is important for brain ageing, and that its function in astrocytes is crucial to preserve brain health and normal neuronal activity.
TBD