Huntington’s disease (HD), a neurodegenerative disorder, is caused by an expansion of a polyglutamine (polyQ) tract near the N terminus of the huntingtin protein (HTT). PolyQ expansion beyond a critical threshold (∼35–40 residues) triggers the ordered aggregation of HTT, leading to the formation of oligomers, fibrils, and large inclusion bodies within cells. A variety of toxic mechanisms are associated with these different aggregate species. As a result, considerable effort has been exerted to develop methods to inhibit or manipulate the aggregation process for therapeutic benefit; however, this has not resulted in an approved drug for HD. HTT also readily binds lipid membranes, altering its aggregation profile and resulting in membrane damage. This suggests that altering the ability of HTT to interact with membranes may represent an additional therapeutic strategy. Using a polydiacetylene assay for screening, a compound, ruthenium red, was identified for its ability to block the binding of HTT to a model lipid membrane. Using a variety of techniques, the ability to alter HTT aggregation and membrane binding was investigated. Ruthenium red reduced fibril formation, alters oligomer structure, and prevents the interaction with membranes. In addition, treatment with ruthenium red ameliorated a motility phenotype in a C. elegans model of HD.
Biswas et al. (Sun,) studied this question.