Huntington’s disease, a fatal neurodegenerative disease, is caused by mutant forms of the huntingtin (htt) protein with an elongated poly-glutamine domain. The ability of htt to bind to and disrupt lipid membranes may be a factor in htt-related toxicity. Small molecules that alter the ability of htt to bind to lipid membranes could represent novel therapeutic agents. Thus there is a need to identify such small molecules. As a result, efforts were made to optimize a simple colorimetric assay for htt/lipid binding based on polydiacetylene (PDA) that can be used as a high throughput screen. When PDA molecules are incorporated into lipid vesicles and polymerized, they are blue. Applying mechanical stresses to PDA molecules, which can be caused by proteins binding to the membrane, induces a color change to red. This colorimetric response can be quantified spectroscopically. Promoters and inhibitors of htt/lipid membrane interactions are identified through a significant deviation from control experiments in which the vesicles are exposed to htt in the absence of small molecules. When potential promoters/inhibitors are identified, the small molecules must be validated. Additional small molecule controls will be performed and the experiment replicated to ensure the validity of the small molecules to significantly alter htt/lipid membrane binding interactions. Validated small molecules can then be used in studying the toxicity mechanism of htt.

Identifying small molecules that modulate the ability of huntingtin to bind membranes

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.