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As an E3 ubiquitin ligase, Ube3a mediates the degradation of specific protein substrates. The gene that encodes Ube3a resides within human chromosome 15q11-13, a heavily imprinted genomic region associated with various neurodevelopmental diseases. When this region is missing in the chromosome inherited from the mother, children develop the developmental disorder Angelman syndrome. In contrast, when this same region is duplicated in the maternal chromosome, the majority of children develop autism spectrum disorder (ASD). Ube3a is the only gene within this chromosomal segment that is consistently expressed from the maternal chromosome. Therefore, these observations suggest that abnormal quantities of Ube3a, whether too high or too low, dictate the onset of neurodevelopmental disorders. Moreover, these observations imply that cells must possess a method to maintain Ube3a levels and enzymatic activity within a physiologically acceptable range. Understanding the factors that control the cellular quantities of Ube3a may provide important insight into the mechanisms of ASD to guide the design of ASD therapeutics as well as methods to diagnose and distinguish ASD subtypes.

Preliminary work by the research team has identified a protein that regulates Ube3a stability, making this the first molecular regulator of Ube3a abundance in the cell. The experiments will allow development of novel pharmacological targets for ASD therapies, and test how genetic manipulation of these targets can alter neuronal development and connectivity. These experiments are expected to provide insight into previously unknown mechanisms of ASD and provide novel targets for the development of therapeutic strategies in ASD.