[
International Worm Meeting,
2003]
C. elegans amenability to genetic analyses and pharmacological screens may uncover aspects of the toxicity of human disease-associated proteins difficult to manipulate in vivo by other means. We have validated a worm-based approach to the study of Huntington's disease pathogenesis. We have observed that huntingtin, the HD protein, is able to interact with C. elegans proteins, and that human homologs of huntingtin interactors in worms may be involved in HD pathogenesis, as shown for the transcriptional regulator CA150, a candidate modifier gene in HD. We have described a transgenic C. elegans model of polyglutamine-dependent neuronal dysfunction without cell death. In this model, polyQ-expanded N-terminal huntingtin fused to fluorescent reporter proteins produces a significant mechanosensory defect at the tail. This phenotype partially correlates with aggregation of fusion proteins in neuronal processes and abnormal morphology of neuronal cell axons. This phenotype can be genetically suppressed with or without a reduction of aggregation, and genetic suppressors are being characterized. As part of a multi-assay neurodegeneration drug screening program coordinated by the NINDS, we have tested a collection of 1040 drugs in our transgenic animals. We have detected a manageable number of confirmed hits that show a dose-dependent restoration of touch sensitivity at the tail. One of these compounds appeared to significantly reduce aggregation in neuronal processes and abnormal morphology of axons in a dose-dependent manner. Our drug screening data suggest that the use of worm mechanosensation allows for a sensitive detection and validation of active compounds, which may be instructive in selecting drug leads.