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, and problems with movement and balance. Deregulation of the expression of a protein called E6 Associated Protein (E6-AP) is tightly associated with AS. E6-AP has been described to have two functions: the first is a function that mainly leads to the degradation of other proteins, and the second, first described by us, is to activate the DNA transcription of other genes through steroid hormones and their receptors like Estrogen Receptor alpha. Up till now, most of the published studies have examined the role of first function of E6-AP in the development of AS and it is not known if the second function of E6-AP plays a role in the pathology of AS. In this grant application, we will examine the role of the transcriptional coactivation function E6-AP through Estrogen Receptor alpha signaling in the development of AS. We have taken an interdisciplinary approach by connecting the steroid hormone-signaling field with neuroscience, from which we expect to find exciting results that would hugely impact future research on both fields. This will provide us with valuable information on the currently unidentified downstream effectors of E6-AP. Identification of pathways that are transcriptionally regulated by E6-AP would also lead to the development of novel targeted molecular therapies for AS. Our novel proposed hypothesis is based on extensive evidence indicating that E6-AP has two important biological roles, which the research community has failed to connect: 1) E6-AP is a known coactivator for Estrogen Receptor and 2) E6-AP is a gene associated with AS. Innovation, in this grant application, is mainly presented by focusing on the transcriptional co-activator function of E6-AP through Estrogen Receptor. We believe that the combination of such an innovative idea with practical standard methodologies will greatly contribute to the feasibility of the proposed studies. This project will provide a prime source for the discovery of new molecular pathways and their role in neuropathology of AS. Accomplishing the proposed studies in this grant will not only provide new insights into the mechanism of action of E6-AP and ER in AS but will also provide promising new therapeutic targets and venues for AS patients.

Publications associated with this funding:

https://pubmed.ncbi.nlm.nih.gov/29388081/

https://pubmed.ncbi.nlm.nih.gov/24091829/