Role of UBE3A in the brain

Angelman syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, seizures and the absence of speech, and it shows a high comorbidity with autism. The syndrome is caused by maternal deletion or mutation of a single gene that encodes ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A typically is silenced in neurons, and therefore the loss of maternal UBE3A results in a complete absence of the protein in most areas of the brain. UBE3A is an enzyme that targets proteins for degradation, a process that maintains normal functioning within cells.

In 2011, Ben Philpot and his colleagues at the University of North Carolina at Chapel Hill discovered that the silencing of the paternal UBE3A allele can be reversed. This suggests a possible therapeutic opportunity. However, in order to design treatment strategies, the researchers must first determine which neuronal functions can be recovered and identify the ideal age range for therapeutic intervention. Philpot hypothesizes that the loss of UBE3A produces defects at the synapses — the connections between neurons — that can be overcome into adulthood. To begin testing this hypothesis, the researchers plan to reinstate UBE3A expression in neurons from Angelman syndrome model mice, and determine the extent to which synapse function recovers.