SUBCELLULAR FUNCTIONS OF UBE3A ISOFORMS DRIVE SYNAPTIC DYSFUNCTION IN ANGELMAN SYNDROME
Genetic defects of the gene encoding the ubiquitin ligase UBE3A cause a severe neurodevelopmental disorder, the Angelman syndrome (AS). The pathophysiology of AS remains unclear, hindering the development of effective therapies. Using AS animal models, we show here that UBE3A controls the development of excitatory and distinct subtypes of inhibitory synapses in cortical pyramidal neurons through cell-autonomous mechanisms, ultimately leading to alteration of synaptic transmission and hyperexcitability. Replacing endogenous Ube3a with individual isoforms, we demonstrate that their uneven nuclear (hUBE3A isoform 1) and cytosolic (hUBE3A isoforms 2/3) distribution is critical for regulating distinct aspects of synaptic development. We also define the molecular requirements underpinning this regulation, showing that: (i) both nuclear and cytosolic UBE3A rely on their ubiquitin ligase activity to ensure proper assembly of synapses; (ii) in addition to the nucleus, UBE3A isoform 1 is also localized in the cytosol, where it is functionally interchangeable with UBE3A isoform 3. Our findings identify a subcellular distribution-dependent mechanism by which UBE3A coordinates cortical circuit development and suggest pathogenic mechanisms of AS.