From UBE3A to Angelman syndrome: a substrate perspective

Abstract

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder that is characterized by motor dysfunction, intellectual disability, speech impairment, seizures and common features of autism spectrum disorders (ASDs). Some of these AS related phenotypes can be seen in other neurodevelopmental disorders (Williams, 2011; Tan et al., 2014). AS patients commonly carry mutations that render the maternally inherited UBE3A gene non-functional. Duplication of the chromosomal region containing the UBE3A gene is associated with ASDs. Although the causative role for UBE3A gene mutations in AS is well established, a long-standing challenge in AS research has been to identify neural substrates of UBE3A, an E3 ubiquitin ligase. A prevailing hypothesis is that changes in UBE3A protein levels would alter the levels of a collection of protein substrates, giving rise to the unique phenotypic aspects of AS and possibly UBE3A associated ASDs. Interestingly, proteins altered in AS are linked to additional ASDs that are not previously associated with changes in UBE3A, indicating a possible molecular overlap underlying the broad-spectrum phenotypes of these neurogenetic disorders. This idea raises the possibility that there may exist a "one-size-fits-all" approach to the treatment of neurogenetic disorders with phenotypes overlapping AS. Furthermore, while a comprehensive list of UBE3A substrates and downstream affected pathways should be developed, this is only part of the story. The timing of when UBE3A protein functions, through either changes in UBE3A or possibly substrate expression patterns, appears to be critical for AS phenotype development. These data call for further investigation of UBE3A substrates and their timing of action relevant to AS phenotypes.

Keywords: Angelman syndrome; UBE3A; autism; neurodevelopmental disorders; ubiquitin ligase.

Figure 1

Diagram of UBE3A substrate cascade to Angelman syndrome. Angelman syndrome is caused by the pathological loss of maternal UBE3A protein expression, resulting in the loss of regulation of its pool of downstream substrates. UBE3A direct interactors/substrates are labeled as a 1° inside a circle. Indirect substrates/changes are labeled as 2° inside a circle. Gene products associated with neurodevelopment are in tan colored circles and associated with Autism spectrum disorders are colored. Following the loss of UBE3A changes to these 1°substrates are the initiators of cascade of events which lead to 2° changes. These 2° changes can be in the form of protein-protein interactions, cell biological, electrophysiological, etc. The convergence of these 2° and downstream changes produce phenotypes characteristic of Angelman syndrome. Given some proteins known to be misregulated in ASDs are primary or secondary interactors in this UBE3A-dependent pathway, as indicated by the colored substrates, the phenotypic overlap between Angelman Syndrome and autism spectrum disorders it is not surprising. Through the study of UBE3A substrates, more overlapping molecular changes underlying shared phenotypes may become apparent.