Efficacy of Increased Ube3a Protein Levels in the Brain in Rescuing the Phenotype of an Angelman Syndrome Mouse

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes an E6-AP ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. Although it was previously believed that UBE3A was imprinted in a brain region-specific manner, primarily in the hippocampus and cortex, recent evidence indicates that there is a widespread knockdown of Ube3a protein throughout the AS mouse brain. As a result, it became necessary to evaluate AS human brain samples to verify the relevance and accuracy of the AS mouse model. It was determined that Ube3a is deficient throughout all major brain regions in humans with AS. The remainder of this dissertation work was focused on determining if increased UBE3A expression in the AS mouse brain would be sufficient to rescue the AS phenotype. The results show that adeno-associated virus-mediated UBE3A delivery is not effective in the AS neonatal brain. In the adult AS mouse brain, however, it increased Ube3a in the hippocampus to near wild-type levels. This was sufficient to rescue the associative fear conditioning learning deficit in the AS mouse and improve learning and memory in the Morris water maze. These studies are the first to demonstrate that increased protein production in the adult AS mouse is sufficient to improve the AS phenotype, indicating that the symptoms of AS are not necessarily embryonic developmental