The E3 Ubiquitin Ligase Ube3A Regulates Synaptic Function Through the Ubiquitination of Arc

Abstract

The E3 ubiquitin ligase Ube3A was initially isolated as a cellularfactor required for the transforming activity of human papillomavirus;however, subsequent studies have implicated this gene in aspects ofhuman cognitive function. Maternal deficiency of Ube3A gives rise toAngelman syndrome (AS), a severe neurodevelopmental disorder, anddysregulation of this gene has also been implicated in autism. However,the specific roles that Ube3A plays in the developing and adult nervoussystem are largely unknown. We find that Ube3A is a neuronalactivity-regulated protein that controls synaptic function byubiquitinating and degrading the synaptic protein Arc. In the absence ofUbe3A, elevated levels of Arc accumulate in neurons, resulting in theexcessive internalization of AMPA-type glutamate receptors at synapsesand impaired synaptic function. These findings suggest that excess Arcexpression may contribute to at least some aspects of the cognitivedysfunction associated with AS.UBE3A encodes an E3 ubiquitin ligase that has been shown to function asan enzymatic component of the ubiquitin-proteasome protein degradationpathway. Although initially identified as a cellular factor required forthe transforming activity of human papillomavirus (Scheffner et al.1993), subsequent genetic studies indicate a critical role for Ube3A inhuman cognitive function. Yet, the precise function of Ube3A duringnervous system development and how Ube3A mutations give rise tocognitive impairment are not clear. After briefly reviewing the evidenceimplicating Ube3A in human cognitive function, we discuss recentfindings from our laboratory concerning the role of Ube3A in regulatingsynaptic development and function (Greer et al. 2010). We find thatexperience-driven neuronal activity induces Ube3a transcription and thatUbe3A then regulates excitatory synapse development by controlling thedegradation of Arc, a synaptic protein that promotes the internalizationof AMPA-type glutamate receptors. We find that disruption of Ube3Afunction in neurons leads to an increase in Arc expression and aconcomitant decrease in the number of AMPA receptors at excitatorysynapses. We propose that this dysregulation of AMPA receptortrafficking may contribute to the cognitive dysfunction that occurs inAngelman syndrome (AS) and possibly autism spectrum disorders (ASDs).