Persistent neuronal stress signalling underlies Angelman syndrome phenotypes.

Angelman syndrome is a severe neurodevelopmental disorder caused by the loss of UBE3A, a gene that encodes an E3 ubiquitin ligase1,2. The mechanisms that underlie Angelman syndrome are not well understood, and in particular, the link between UBE3A substrates and disease phenotypes remains uncertain3. Here, using gain- and loss-of-function mutations in UBE3A4,5 along with unbiased proteomics, we show that asparagine synthetase (ASNS) is a target of UBE3A. We find that ASNS protein abundance is increased in the brains of Ube3a-null mice and in human neurons6. Genetic correction of ASNS overabundance rescues microcephaly and many behavioural deficits. Detailed molecular analyses show that ASNS overabundance activates stress signalling and causes a global reduction in neuronal protein synthesis. Our results suggest that loss of UBE3A traps neurons in a state of persistent stress and stunts neuronal growth during developmentally sensitive periods. Moreover, our results indicate that targeting ASNS and the stress response could hold therapeutic potential in Angelman syndrome.