A matter of perspective The multifaceted role of UBE3A in Angelman syndrome development

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutation or deletion of the UBE3A gene, which encodes an E3 ubiquitin protein ligase. E3 ligases are essential components of the UPS (ubiquitin proteasome system). The UPS is a finely tuned machinery that has an essential role in cellular homeostasis, and any perturbation of the UPS may lead to irreparable cellular damage. In this thesis we have employed molecular and biochemical techniques to unravel how the loss-of-function (deletion or mutations) of the E3 ubiquitin protein ligase UBE3A results in AS development, with emphasis on the identification and characterization of brain-specific targets of UBE3A. Using protein-protein interaction techniques we have identified several bona fide UBE3A interacting proteins, among which a pre-synaptic protein. Detailed biochemical and mutational analyses of these proteins have provided the first insights into the intracellular pathways where UBE3A exerts its function. By studying the localization of UBE3A isoforms we uncovered that UBE3A is predominantly localized in the nucleus and that AS-linked mutations can disturb nuclear localization. These observations suggest that UBE3A has an important role in the nucleus, providing further direction for future studies on the relation between UBE3A subcellular localization and the pathophysiology of AS.