Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Autism Risk Identified with Regulatory Sites on the UBE3A Protein


Nature  526, 50–51 (01 October 2015)

Neurodevelopmental disease: A molecular tightrope

Ype Elgersma


The identification of a regulatory site on the UBE3A protein that can be phosphorylated to alter its enzymatic activity provides insight into the aetiology of two human neurodevelopmental diseases, Angelman syndrome and autism.

Duplications of the UBE3A gene cause the neurodevelopmental disorder, autism, which is characterized by impaired social communication and a tendency to engage in repetitive behaviours. The mechanism by which UBE3A activity is regulated in the brain has been poorly understood. Writing in Cell, Yi et al. report that phosphorylation dynamically regulates this enzyme.

Humans have two copies of most genes, one inherited from each parent. Typically, cells express both copies equally. However, in the case of UBE3A, the paternally inherited gene is almost entirely silenced in neurons, suggesting that UBE3A dosage is crucial for its function in these cells. Indeed, whereas mutations that reduce expression of the maternally inherited UBE3A gene are responsible for Angelman syndrome, duplication of the maternal-chromosome region in which UBE3A resides is associated with Dup15q syndrome, which involves developmental delay, autism, speech deficits and epilepsy. Having more than two copies of this maternal-chromosome region leads to an almost-certain chance that the individual will develop autism.

The authors then discovered that a threonine amino-acid residue (dubbed T485) in this region is an acceptor site for phosphates — groups that are covalently added to proteins by kinase enzymes to modulate the proteins' activity. Specifically, T485 is phosphorylated by protein kinase A (PKA), which is a well-known modulator of synaptic plasticity (changes in the strength of the synaptic connections between neurons) and cognitive function.

This is a notable finding, given the wealth of data linking synaptic dysfunction to autism. Moreover, Yi et al. identified the T485 mutation in a child with autism, highlighting the potential human relevance of this regulatory mechanism.

More genetic evidence is needed to precisely quantify the risk of autism associated with UBE3A phosphorylation at T485. Nonetheless, Yi and colleagues' findings provide a compelling model to explain the narrow range of tolerance for UBE3A activity during neuronal development, and the concomitant risk of Angelman syndrome and autism when tight control of the enzyme's activity is lost.

This model of UBE3A regulation opens up fresh avenues of investigation. The interplay between the PKA signalling pathway and UBE3A should now be fully explored. Of particular interest is the extent to which the role of PKA in synaptic plasticity and cognitive function is mediated through UBE3A phosphorylation.

Additional human-genetics studies should be performed to determine whether other mutations in the PKA pathway are also associated with autism. And finally, it is important to determine whether stimulating PKA-dependent phosphorylation of UBE3A might be beneficial to people with autism. Drugs known as phosphodiesterase inhibitors are well-known stimulators of the PKA pathway, and could be used to test this.

Further investigation into the regulation and function of UBE3A has the potential to yield insights into the mechanisms that underlie a range of neurodevelopmental disorders, from epilepsy to intellectual disability and autism.

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