Angelman syndrome is a rare disease with a single known cause: one missing gene. The lack of that gene, normally inherited from the mother, occurs in approximately one in 20,000 births and is associated with cognitive and mobility deficits that become evident in children when they are around 6 months of age.
While the cause of the syndrome seems simple, it is not well understood why the absence of the gene has the effects that it does. That has made treatments for the condition elusive.
New research from Jason Yi, PhD , an assistant professor of neuroscience at Washington University School of Medicine in St. Louis, has found in mice that the missing gene is the first domino in a biological sequence that leads to a normally harmless enzyme accumulating in the brain. The buildup is not harmful on its own but appears to have indirect effects that ultimately impair brain growth.
The study was published Oct. 21 in Nature .
“The neurons are tricked into thinking that they’re in stress when they’re not — that’s bad because they will then not grow normally,” Yi said, noting that most children with Angelman syndrome have smaller brains than do their peers of the same age. “It’s a reaction from the brain trying to conserve resources to protect itself. It does suggest that there is a dysregulation in the brain we might be able to correct.”
Indeed, Yi’s team found that righting one of the downstream dominoes in the molecular cascade of Angelman syndrome re-established healthy brain development and behaviors in mice.
The findings are the first time that an increase in this enzyme — asparagine synthetase — was linked to a neurological condition. The finding adds to a growing body of scientific evidence that protein imbalances, even when they aren’t directly damaging cells, can trigger stress responses that can lead to neurodevelopmental disorders.
The path from the missing gene in Angelman syndrome to the stress response is not direct. The gene, called UBE3A , produces an enzyme called ubiquitin ligase, a housekeeping protein that marks unneeded proteins in cells for disposal. Ubiquitin ligase is active throughout the brain and is involved in 60 different cellular processes.
To narrow down which of those 60 were related to Angelman’s syndrome, Yi and his team developed modified cells in the lab in which the UBE3A gene was deactivated.
In these experiments, they identified 23 candidate proteins that increased in the absence of the gene. Of these, one had a strong link to ubiquitin ligase’s normal housekeeping function: asparagine synthetase. This is yet another enzyme that helps cells produce essential proteins.
Yi and his colleagues showed in mice that were genetically modified to develop Angelman syndrome that elevated levels of asparagine synthetase activated the brain’s stress response. The finding was surprising because the enzyme does not interact with normal triggers for the stress response, and because the overabundance of the enzyme does not otherwise damage the cell.
This stress response leads to a dramatic reduction of protein production and growth as the brain tries to conserve resources.
When Yi and his team blocked the production of asparagine synthetase, they found that normal brain growth was restored.
Yi said the stress response triggered by asparagine synthetase could be targeted by medications, but much remains to be learned before work on a possible treatment can begin.
The team is working to further characterize precisely why asparagine synthetase triggers the brain’s stress response and to map where in the brain the stress response is most active and when during development medical interventions would be most effective.
“We still don’t know a whole lot about the disease,” said Yi. “We haven’t been able to identify all of the things that the missing gene is doing and rescue the things that it is not doing in Angelman’s syndrome. But I think our data are the most complete so far to begin answering those questions.”
Kim, K-S, Gardner C, Cullen A, Stelzer JA, Cho K, Sharma A, Nemera MT, Law T, Naz H, Zhao G, Gabel HW, Patti GJ, Musiek ES, Ahn T-H, Yi JJ. Persistent neuronal stress signaling underlies Angelman syndrome phenotypes. Nature . October 21, 2026. DOI: 10.1038/s41586-026-11165-4TK .
Support for this work came from the Simons Foundation (Bridge to Independence award #387973), the Whitehall Foundation, the Hope Center for Neurological Disorders at Washington University (Pilot Award), and the National Institute of Mental Health (R01MH122786 and R01MH144153). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Nature
Persistent neuronal stress signaling underlies Angelman syndrome phenotypes
21-Oct-2026