Development of an in vivo, screenable, split-luciferase based model of huntingtin multimerization

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon one of the gene that encodes for the protein huntingtin (HTT). PolyQ expansion drives HTT aggregation into multimeric species that range from soluble oligomers to fibrillar, insoluble inclusion bodies. Cellular mechanisms facilitating HTT aggregation are incompletely understood, hindering efforts to develop strategies that prevent inclusion body formation or promote clearance of misfolded protein. To enable future unbiased in vivo screening approaches to identify genetic modifiers and pharmacological strategies to suppress HTT aggregation, we have developed HTT^LUM, a split-luciferase-based detector of HTT-HTT interaction in adult Drosophila melanogaster neurons. This system permits real-time monitoring of HTT multimerization in living, active flies. The non-lethal nature of the HTT^LUM system enables subsequent analysis of HTT aggregation, neurotoxicity, and other phenotypes in the same flies, thus serving as a platform for medium-throughput screening followed by mechanistic validation of potential modifier candidates.