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This grant will launch an exciting collaboration with Dr Darragh O’Brien, Head of Structural and Mechanistic Proteomics, to run a ubiquitomic study to identify novel substrates of the E3 ligase IDOL, which is a promising therapeutic target for Alzheimer’s disease.

Regulation of E3 ligases and ubiquitination of proteins is a regulatory mechanism implicated in a number of diseases. IDOL is an E3 ligase that regulates levels of the low density lipoprotein receptor (LDLR) which impacts uptake of lipids. In the brain, the LDLR may impact the clearance of the main late onset Alzheimer’s disease risk gene ApoE4, and published reports have demonstrated that inhibition of the E3 ligase IDOL leads to decreased Alzheimer’s disease (AD) associated pathology in mouse models. With the help of this funding we hope to uncover novel IDOL interacting partners and substrates which we anticipate will lead to a greater understanding of how IDOL regulates AD pathology. This work will build on a larger drug discovery program that is generously funded by the Rainwater Charitable Foundation.