Persistent neuronal stress signalling underlies Angelman syndrome phenotypes.

Loss of UBE3A causes increased ASNS protein levels, activating stress signalling and reducing neuronal protein synthesis in Angelman syndrome models.

• Why it matters: Understanding the molecular mechanisms underlying Angelman syndrome is crucial for developing targeted therapies, as the link between UBE3A substrates and disease phenotypes remains unclear.
• What they did: The study used gain- and loss-of-function UBE3A mutations and unbiased proteomics to identify ASNS as a UBE3A target, observing increased ASNS in Ube3a-null mice and human neurons, and correcting its overabundance rescued key deficits.
• The result: Overabundant ASNS triggers stress signalling and impairs neuronal growth, suggesting that targeting ASNS and stress responses may offer therapeutic strategies for Angelman syndrome.