Blocking the ability of huntingtin to bind membranes: a therapeutic strategy for Huntingtons disease

Abstract The ordered aggregation of proteins into amyloid fibrils is a hallmark of numerous neurodegenerative diseases. A common strategy in developing therapeutics for amyloid-based diseases relies on preventing or manipulating the aggregation process. However, many amyloid-forming proteins and their aggregates bind and damage organelle and cellular membranes. As such, blocking the ability of these proteins from directly interacting with membranes represents a unique therapeutic strategy. Using a mutant huntingtin (htt) protein associated with Huntington’s disease (HD) as a model system, the viability of this strategy was evaluated. Screening over 1200 compounds for their ability to block htt binding to lipid vesicles, two compounds, Ro90-7501 (Ro) and Benzamil (Ben), were identified and validated. Despite directly interacting with htt, neither compound prevented fibril formation. Molecular dynamics simulations suggested each compound has a unique mechanism of action, consistent with experimental data. Importantly, both compounds ameliorated phenotype in a C. elegans model of HD.