The Christina Castellana FAST Postdoctoral Fellowship Award: Targeting Upstream Regulators of Ube3a in Angelman Syndrome | $164,000

As an E3 ubiquitin ligase, Ube3a catalyzes a reaction to label certain proteins in the cell so that they are targeted for degradation. Mutations that abolish this activity are sufficient to cause Angelman syndrome (AS). Typically, ubiquitin ligases recognize several substrates, and numerous substrates of Ube3a have been proposed. Thus, Ube3a likely regulates an ensemble of proteins that contribute to AS pathogenesis, and therefore, targeting individual components of this group for AS therapies may not be sufficient to alleviate neurological deficits associated with AS. Increasing evidence suggests that abnormal variations in the quantity of Ube3a itself may be at the heart of neurodevelopmental diseases. UBE3A resides within chromosome 15q11-13, a heavily imprinted genomic region associated with a variety of neurodevelopmental disorders. In the brain, Ube3a is only expressed from the chromosome inherited from the mother. Children who inherit a maternal chromosome carrying a deletion in 15q11-13 develop AS, whereas the majority of children who inherit a maternal chromosome carrying duplications in 15q11-13 develop Autism spectrum disorder. Therefore, understanding the factors that control the cellular quantities of Ube3a may provide an effective strategy for the design of AS therapeutics. My preliminary work has found that Ube3a stability is subject to regulation by enzymes that act upstream of Ube3a. This identifies for the first time biological mechanisms within cell that function to maintain cellular Ube3a quantities. I have proposed a system of experiments that investigates how Ube3a misregulation leads to learning defects in individuals with AS. My approach will use recent advances in biosensor development as well as sophisticated microscopy techniques to visualize directly in the brain how loss of Ube3a function perturbs normal events that occur during learning and memory at synapses. Moreover, these experiments will simultaneously allow me to identify pharmacological targets for AS therapy, and test how manipulation of these targets affects the properties of neurons lacking Ube3a. I expect that these experiments will provide insight into previously unknown mechanisms of AS pathogenesis and provide novel targets for the development of therapeutic strategies in AS. The ultimate goals of these studies is to (1) identify the molecular causes of AS by understanding Ube3a regulation and (2) using this information, develop potential pharmacological strategies for AS treatment.

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