Persistent neuronal stress signalling underlies Angelman syndrome phenotypes.

Loss of UBE3A causes excess ASNS protein, which activates neuronal stress signalling, inhibits neuronal growth, and drives Angelman syndrome phenotypes. The study combined UBE3A gain- and loss-of-function mutations with unbiased proteomics and found increased ASNS protein in Ube3a-null mouse brains and human neurons. Genetic correction of ASNS overabundance rescued microcephaly and multiple behavioural deficits; ASNS overabundance also globally reduced neuronal protein synthesis, suggesting that targeting ASNS and the stress response has therapeutic potential.