Abstract
BackgroundLoss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A’s localization is integral to its function.MethodsWe used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals.ResultsWe demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals.ConclusionsBy highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder.
Highlights
Loss of Ubiquitin-protein ligase E3A (UBE3A) causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism
GABAergic deficits have been implicated in the pathogenesis of neocortical hyperexcitability and epilepsy in Angelman syndrome (AS) model mice [25, 48], and γAminobutyric acid (GABA) transporter-1 has been proposed as a potential UBE3A substrate [49]
To determine whether UBE3A is expressed in inhibitory neurons of the human neocortex, as it is in mice, we performed double labeling with GABA (Fig. 4)
Summary
Loss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. Protein degradation through the ubiquitin-proteasome pathway (UPP) is important for a wide range of functions in the nervous system [1, 2]. In UPP processing, the protein substrate is marked by covalent attachment of the small protein ubiquitin for subsequent degradation by the proteasome, a specialized proteolytic complex. UBE3A, the first E3 discovered in the HECT class [5], is of special interest, because failure to maintain appropriate levels of UBE3A in the brain is directly linked to severe clinical disorders. On the other hand, increased UBE3A activity (via gene duplication or gain-of-function mutation) is implicated in several forms of autism [9,10,11,12,13,14,15], implying that UBE3A must be expressed at precise levels to allow proper neuronal function
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