Presynaptic Ube3a E3 ligase promotes synapse elimination through down-regulation of BMP signaling

Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in Drosophila neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome–associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation. The ubiquitin ligase Ube3a has been associated with neurodevelopmental disorders. Its inactivation causes the developmental disorder Angelman syndrome, and increased Ube3a activity is associated with autism spectrum disorder. Furusawa et al . investigated the role of Ube3a at the presynaptic level, reasoning that synaptic abnormalities during development might be responsible for the occurrence of these disorders. Using fruit fly models, the authors showed that Ube3a is responsible for axonal presynapse elimination and function. High levels of Ube3a at the axon terminals led to precocious presynapse elimination, whereas elimination from axon terminals due to localization defects was associated with defects in normal presynapse elimination. The results potentially explain the mechanism mediating the development of disorders such as Ube3a-mediated Angelman syndrome and autism spectrum disorder. —Mattia Maroso Physiological and pathological impacts of presynaptic Ube3a E3 ligase activity on synapse elimination are elucidated.