Date of Graduation
Eberly College of Arts and Sciences
Huntington disease is an autosomal dominant neurodegenerative disorder. The abnormally long CAG-repeats in the huntingtin gene that encode an expanded polyglutamine stretch which promotes self-assemble of huntingtin into different aggregation species that are disease related. Huntingtin intimately interacts with a variety of lipid membranes. Lipid composition is altered in HD, especially cholesterol content. Here we investigate how cholesterol content modulates the interaction between huntingtin and lipid membranes. TBLE/PDA binding assay is performed to test the binding affinity of huntingtin with lipid bilayers containing different amount of cholesterol. As the cholesterol content increases, the extent of huntingtin binding to lipid bilayers decreases. Also, atomic force microscopy (AFM) is used to directly monitor the formation of aggregates on supported lipid bilayers containing exogenously added cholesterol. Morphological and mechanical changes in the bilayers exposed to huntingtin are observed by the presence of cholesterol. On pure TBLE, globular aggregates are formed and grainy in appearance. Most of the bilayers are disrupted. In contrast, lipid bilayers enriched in different amount of cholesterol facilitate the formation of plateau-like aggregates with a smooth appearance. With the increase of cholesterol content in lipid bilayers, the percentage of the surface disrupted by the protein aggregation decreases. In sum, the presence and amount of cholesterol in lipid bilayers modulates the huntingtin binding and aggregation on lipid membranes.
Gao, Xiang, "Cholesterol Modulates Huntingtin Binding to and Aggregation on Lipid Membranes" (2015). Graduate Theses, Dissertations, and Problem Reports. 5646.