Oligomerization enhances huntingtin membrane activity but is suppressed by covalent crosslinking

Huntingtin disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine (polyQ) tract within the huntingtin (htt) protein, leading to aggregation into a variety of species ranging from small oligomers to large fibrils. A consensus concerning which of these aggregate states are primarily responsible for toxicity associated with mutant htt remains elusive. Htt directly binds and damages a variety of membranous surfaces within cells. Here, the ability of different aggregation states of htt to interact with and damage lipid membranes was determined. Oligomers represented the most active lipid binding species, whereas, fibril formation severely limited membrane binding. Thus, strategies to stabilize oligomers were implemented, and conformational flexibility appeared to play a key role in the oligomer/membrane interaction. In particular, stabilizing oligomers with covalent crosslinking with 1,5-difluoro-2,4-dinitrobenzene (DFDNB) effectively eliminated the ability of oligomers to bind lipid membranes and reduced their associated cellular toxicity.