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Reducing enzyme excess eases some symptoms in Angelman model mice

Excess of a common enzyme activated a cellular stress response in an Angelman syndrome mouse model. Bringing its level closer to normal improved brain growth and some behaviors, but left movement coordination and sleep problems unresolved. The peer-reviewed study identifies a partial disease mechanism, without testing a treatment in people.

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An enzyme accumulates

Excess of the enzyme asparagine synthetase is linked to impaired brain growth in an Angelman syndrome mouse model. A peer-reviewed study connects the accumulation to persistent stress signaling in neurons.[1], [2]

Angelman syndrome involves loss of neuronal function of the maternally inherited UBE3A gene, which helps regulate protein degradation. The researchers found elevated levels of asparagine synthetase, also called ASNS, in the mouse brain. Earlier patient-derived neuron data also showed accumulation. This identifies a possible downstream consequence of lost protein regulation, rather than replacing the genetic explanation of the syndrome.[1]

Normalization gives a partial rescue

Genetically bringing enzyme levels closer to normal throughout development improved brain weight and protein synthesis, alongside several behavioral measures. Sleep, general locomotion and coordination on a rotating rod did not recover. The excess enzyme activated an integrated stress response that suppresses protein production. Its involvement of a different stress-sensing branch from the usual amino-acid-starvation response matters because amino acids were elevated rather than depleted.[1]

The remaining biological question

The experiment did not establish whether asparagine itself or another consequence of enzyme accumulation drove the stress signal. Nor did it test a treatment in people. Losing both copies of ASNS can itself cause developmental disease, so reducing an excess cannot be equated with eliminating the enzyme. The unresolved symptoms also show why this mechanism explains only part of the mouse phenotype.[1]

For more information on this topic, you can read the related columns.

References

  1. News sourceNatureExcess neuronal stress explains some Angelman-model symptoms↩1↩2↩3↩4
  2. News sourceWashU MedicineEnzyme accumulation affects brain growth in an Angelman model↩
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