Screen for Genetic Modifiers of Neurotoxicity Caused by Expanded Huntingtin
The goal of this project is to identify novel therapeutic targets for Huntington's disease. The approach is to carry out biased screens for genetic modifiers of expanded huntingtin-induced neurodegeneration using both full-length and N-terminal HD Drosophila models that are well established. We have set-up a robust behavioral assay as well as other validating assays that are quantitative, and have been used before successfully in pilot dosage-sensitive screens.
The proposed biased genetic screen will focus on selected, high-quality, collections of candidate modifier genes. One collection comprises genes encoding the huntingtin interactome, which we previously showed to be enriched for genetic modifiers. A second collection comprises the top primary hits of a cell-based “drugable genome” screen of polyglutamine-dependent apoptosis. The third collection comprises a list of proteases previously tested against huntingtin in cell-based and/ or western blot assays.
This genetic screen in HD Drosophila models provides an opportunity to validate in vivo hits from cell-based and in vitro screens of the “drugable” genome before embarking in costly and time-consuming validation in mouse models. Furthermore, the Drosophila HD models also allow to screen close to saturation the huntingtin interactome, a project that is currently not practical in the mouse.
Relevance of the project to IDDRC mission:
Huntington's disease leads to severe cognitive and neurological impairments. Identifying molecular pathogenic mechanisms and genetic modifiers relevant to Huntington 's will facilitate the development of therapies for this devastating disease.