Novel Locomotion-based Validation Assay for Candidate Drugs Using Drosophila DYT1 Disease Model.

摘要

We have established fly lines expressing a mutant form of human torsinA (torsinA E) in fly brains. We have shown that (1) human torsinA E protein is expressed in fly brains; (2) expression of human torsinA E dominantly suppresses larval locomotion and GTPC cyclrohydolase protein levels; (3) supplementation of dopamine can partially rescue the locomotion defects of Drosophila larvae caused by the expression of human torsinA E. These results demonstrated that human torsinA can cause locomotion defects and reduction of GTP cyclohydrolase proteins very similar to the phenotypes in dtorsin-null larval brains. These results suggested that we can study the molecular defects of human torsinA E using our fly model system. We have submitted a manuscript describing our results. We have conducted preliminary RNAi screen to identify modifiers of dtorsin-null locomotion defect phenotype. Our preliminary results suggest that (1) dopamine signaling pathway; (2) RNP transport pathway; (3) axon guidance pathway; and (4) other early-onset dystonia genes as candidates for modifiers. These RNAi screen will be very useful for identifying potential therapeutic targets of early-onset dystonia patients.