Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of maternal UBE3A, an E3 ubiquitin ligase essential for neuronal development, synaptic plasticity, and cognitive function. AS has traditionally been viewed as a cell-autonomous disorder in which intracellular UBE3A deficiency drives neuronal dysfunction. However, recent evidence suggests that impaired extracellular vesicle (EV)-mediated intercellular communication also contributes to disease pathophysiology. EVs are key intercellular mediators of neuronal and glial signaling, as they transfer proteins, lipids, and nucleic acids, which regulate synaptic homeostasis, circuit maturation, and brain plasticity. Here, we discuss emerging evidence linking UBE3A deficiency to alterations in EV biogenesis, cargo composition, secretion, and uptake. We propose that disruption of ubiquitin-dependent endosomal trafficking, together with endolysosomal dysfunction involving LAMTOR1 and the lysosomal Ca2+ channel TRPML1, contribute to defective EV properties in AS. Moreover, the recent identification of UBE3A within neuronal EVs raises the possibility that loss of EV-mediated UBE3A transfer represents an additional non-cell-autonomous mechanism underlying synaptic dysfunction in AS. These findings support a revised model in which impaired EV signaling amplifies the consequences of intracellular UBE3A deficiency. Finally, we discuss the therapeutic potential of EVs. The ability of wild-type neuron-derived EVs to rescue synaptic and cognitive deficits in an AS mouse model highlights the use of EVs as a promising therapeutic avenue for Angelman syndrome and other neurodevelopmental disorders.

Angelman syndrome, Autonomous mechanism, Neurodevelopmental disorder