Voor het Angelman Syndroom

First Grants 2014

logoASAsponsoredbyDr. Ben Distel – Project amount €120.000,- Start June 2015 – End July 2017 Understanding how UBE3A is regulated and which proteins UBE3A itself regulates, is critical for understanding how UBE3A loss causes AS. This project will identify critical E6AP target(s) in the brain, study the regulation of the levels and activity of the E3 ligase and characterize UIPs which may be critical targets of UBE3A or critical regulators of UBE3A. UIPs may thus represent key drugable targets for potential therapeutics for AS.

During this research, newly identified proteins that interact with UBE3A in a two-hybrid assay will be validated in a highly innovative bacterial system where the eukaryotic ubiquitin system has been reconstituted, or in HEK293 cells where UBE3A will be downregulated. As three of the UIPs are already known to interact with UBE3A’s N-terminal region, patient mutations that are present in this region of UBE3A will be tested to see if they affect interaction with the UIPs. UIP2 has been shown to interact with the region on UBE3A that is bound by the viral activator E6. Thus the PIs proposed to further characterize the UIP2-UBE3A interaction to determine if UIP2 is an activator of UBE3A. This project is innovative and well designed with strong preliminary data. The UIPs are intriguing, especially given the preliminary results with UIP2 as a potential activator of UBE3A. These studies are likely to have a significant impact on our understanding of UBE3A and of AS.


logoASAsponsoredbyDr. Geeske van Woerden – Project amount €115.000,- Start June 2015 – End July 2017 This project will characterize Ube3a Interacting Proteins (UIPs) identified by a collaborator using the 2-hybrid system in the mouse brain and in neuronal cultures. This is a very important project that aims to identify Ube3A substrates. Dr. Van Woerden is collaborating with Dr. Distel who has indentified a number of UIPs. This research has the potential to have a high impact and advance the Angelman field.

During this project, the PI will characterize Ube3a interacting proteins (UIPs) identified by a collaborator in a 2-hybrid approach. The PI will determine if these UIPs are overexpressed in the AS mouse which is a critical experiment to conduct to determine if these UIPs may contribute to the AS phenotypes. However the subsequent experiments involve overexpression UIPs to see if there are effects on neuronal morphology and function in vitro and in vivo. The use of in utero electroporation is fairly novel.