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Persistent neuronal stress signaling underlies Angelman syndrome phenotypes

ABSTRACT: Angelman syndrome is a severe neurodevelopmental disorder caused by loss of UBE3A, a gene that encodes an E3 ubiquitin ligase. 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. Our results suggest that UBE3A operates in neurons to clear stress signaling, and our resultsfurther suggest that ASNS and the integratedthe stress response are potential therapeutic targets in Angelman syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE319851 | GEO | 2026/09/02

REPOSITORIES: GEO

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