The Transcriptional Coactivation Function of E6-Associated Protein in the Brain: Novel Insights into the Pathobiology of Angelman Syndrome

of a dissertation at the University of Miami. Dissertation supervised by Zafar Nawaz, Ph.D. No. of pages in text. (92) Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2 -15q13 region of chromosome 15. The E6-associated protein, E6AP (an E3 ubiquitin protein ligase enzyme) gene, UBE3A is located in this region and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e.g. autism and Rett syndromes). We have shown that E6AP also acts as a coactivator of the estrogen receptor (ER). ER is a ligand-induced transcription factor that exerts potent and wide-ranging effects on the developing brain. Furthermore, the expression pattern of ER in the brain overlaps with that of E6AP. Up till now, all the published studies have examined the role of the ubiquitinprotein ligase activity of E6AP in the development of AS and it is not known what role the coactivation functions of E6AP and ER plays in the pathology of AS. In this thesis work we demonstrate that: E6AP and ERα co-immunoprecipitate and are in the same protein complex in Neuro2a cells. In addition, they colocalize in nuclear and cytoplasmic compartments of the mouse hippocampal neurons and