UBE3A encodes the HECT domain-containing E3 ubiquitin ligase, UBE3A, an enzyme which catalyzes the attachment of ubiquitin to substrate proteins, thereby targeting them for proteasomal degradation. Because of tissue-specific imprinting, UBE3A expression from the paternal allele is silenced in neurons, meaning that all UBE3A expression is contributed by the maternal allele in these cells. This expression feature renders neurons and, by extension, brain circuits acutely vulnerable to genetic disruptions in or near the maternal UBE3A allele. In fact, such maternal UBE3A disruptions cause Angelman Syndrome (AS)- a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, absence of speech, inappropriate emotional affect, and increased seizure susceptibility. Several studies of AS model mice (Ube3a[m-/p+]) have revealed that aberrant excitatory synapse maturation and synaptic plasticity may underlie neurodevelopmental phenotypes in AS. However, how Ube3a deficiency contributes to synaptic dysfunction in Ube3a[m-/p+] mice is largely unknown. Answers to two key questions would greatly enhance our understanding of the relationship between Ube3a and synaptic dysfunction in AS: 1) what is the cell-autonomous role of Ube3a in neurons in regard to synaptic function? and 2) what are the neuronal substrates of Ube3a, and how do they influence synaptic function in the absence of Ube3a? To address the first question, I will use viral vectors in wild-type mice to knock down Ube3a expression in only a sparse population of neurons. Because the circuit environment surrounding these neurons will be normal, I can be sure that their synaptic deficits are caused by their intrinsic loss off Ube3a. To address the second question, I will employ biochemical and proteomics-based approaches to discover novel Ube3a substrates in neurons. Knowledge of these substrates should provide insight into the molecular pathways that are disrupted in Ube3a-deficient neurons and may reveal targets for therapeutic intervention in AS.
Angelman Syndrome (AS) is a severe neurodevelopmental disorder that is primarily caused by neuron-specific loss of the HECT domain-containing E3 ubiquitin ligase gene, UBE3A. Interestingly, overexpression of UBE3A has been linked to autism, another neurodevelopmental disorder. The experiments outlined in this proposal will help to reveal cell-autonomous roles for Ube3a in regulating synaptic function, and, in turn, lend insight into the etiology of AS and autism.
|Judson, Matthew C; Sosa-Pagan, Jason O; Del Cid, Wilmer A et al. (2014) Allelic specificity of Ube3a expression in the mouse brain during postnatal development. J Comp Neurol 522:1874-96|