Excess enzyme activates stress response in Angelman syndrome

Mouse study sheds light on the biological pathway that could underpin brain impairments in Angelman syndrome, potentially revealing a new therapeutic target.

Angelman syndrome is a rare neurodevelopmental disorder caused by the loss of a single gene, UBE3A. How this genetic defect leads to the range of symptoms associated with the condition is largely unknown. Scientists at Washington University School of Medicine in St Louis, Missouri, have now discovered that mouse neurons lacking UBE3A accumulate the enzyme aparagine synthetase (ASNS), which then triggers a cellular stress response. Their findings also show that reducing the levels of ASNS in these neurons reversed symptoms associated with Angelman syndrome.

'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,' explained Dr Jason Yi, the senior author of the study published in Nature.

Angelman syndrome is caused by a loss-of-function mutation in the maternal copy of the UBE3A gene. The paternal copy is already inactive, as it is silenced due to genomic imprinting. Symptoms do not manifest until the child is around six to 12 months old, and include intellectual disability, behavioural and motor difficulties, facial dysmorphia and a smaller brain size.

UBE3A encodes an enzyme which functions as a cellular housekeeper: it marks proteins which are no longer needed for degradation, ensuring that they do not accumulate within the cell. In this study, ASNS was the only protein biologically linked to this enzyme whose levels rose in mouse neurons lacking the UBE3A gene.

In turn, the buildup of ASNS triggered the integrated stress response pathway, a molecular cascade that results in cells lowering their overall protein production to conserve energy. In the mouse models, this neurological stress response ultimately stunted brain growth, potentially providing an explanation for the smaller brain size seen in people with Angelman syndrome.

Previous proposed treatments for Angelman syndrome include a gene therapy that uses CRISPR to switch on the inactivated paternal copy of UBE3A (see BioNews 988). In the new study, however, reducing the amount of ASNS in mouse neurons restored normal brain size. While these results suggest that the enzyme could be an alternative therapeutic target, more research will first be needed to better understand how and why ASNS triggers the brain's stress response.

'We still don't know a whole lot about the disease,' said Dr 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 syndrome. But I think our data are the most complete so far to begin answering those questions.'