Persistent neuronal stress signaling underlies Angelman syndrome phenotypes

The mechanisms underlying this disorder are not well understood, and the link between UBE3A substrates and disease phenotypes remains uncertain. Here, we identify asparagine synthetase (ASNS) as a novel target of UBE3A.

We find that ASNS protein levels are elevated in brains of Angelman syndrome model mice, and metabolomic analysis revealed these animals possess imbalanced amino acid levels leading to a persistent activation of the integrated stress responseincrease in stress signaling and a global reduction in neuronal protein synthesis. When ASNS levels were genetically reduced in mutant animals, stress signaling and protein synthesis rates were corrected, and many behavioral and neuroanatomical deficits were rescued.