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 ligase^1,2. 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 UBE3A^4,5 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.