The Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of the maternally expressed UBE3A gene, which encodes an E3 ubiquitin ligase. Although considerable efforts have been put to dissect UBE3A function in the brain, the pathogenic mechanisms remain largely unknown and effective treatments are not available yet. Being an E3 ubiquitin ligase, defective ubiquitination, which may occur in either nuclear or cytosolic compartments, is thought to be a primary mechanism underlying synaptic dysfunction in AS. Increasing evidence indicates a tight functional interplay between ubiquitination and other post-translational modifications (PTM), including sumoylation, an ubiquitin-related PTM consisting in the covalent conjugation of Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins. In the brain the SUMO machinery finely modulates synaptic and extrasynaptic pathways that are fundamental to neuronal circuit formation and function. In this project, we test the hypothesis that altered ubiquitination might lead to aberrant sumoylation, thus contributing to AS pathogenesis. To explore this possibility, we are currently evaluating sumoylation of nuclear and cytosolic fractions obtained from cortices of AS and wild type mice throughout neurodevelopment. Using the same experimental approach, we are also investigating sumoylation in human cortical neurons obtained from patient-derived induced pluripotent stem cells (iPSCs). Strikingly, preliminary data indicate that both SUMO1- and SUMO2/3 conjugation is impaired at different developmental stages in the nucleus and in the cytosol of AS cortices. These data might unveil a novel pathogenic mechanism of AS and provide the rationale to develop new therapeutic strategies to treat AS patients.