The Role of Electrostatics on Huntingtin Oligomer Membrane Binding: Implications for Huntington’s Disease

Rachel Hankin* and Justin Legleiter
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506

Presentation No.: 103

Assigned Category (Presentation Format): Physical Sciences (Poster Presentations)

Student’s Major: Chemistry; Molecular Biology

Huntington’s Disease (HD), a fatal neurodegenerative disease, is caused by expansion of a polyglutamine repeat segment in the huntingtin protein (htt). This expansion leads to aggregation into oligomers and fibrils. Htt associates with lipid membranes in cells, which influences aggregation and results in membrane disruption associated with toxicity. Understanding this membrane interaction can lead to novel therapeutic strategies for HD. To determine the role of htt oligomers in membrane-binding, oligomers were stabilized with peptide-based fibrillization inhibitors. These peptides were derived from the first 17 amino acids of htt (Nt17), a lipid binding domain that can be used to alter the overall charge of the oligomers. The peptides were phosphorylated or acetylated to mimic known post-translational modifications of htt that are naturally-occurring in cells. The ability of the peptides to stabilize oligomers was verified by atomic force microscopy. Based on a PDA binding assay, increasing the anionic character of oligomers decreased the interaction of oligomers with membranes. As aggregation can interfere with the PDA signal, a sedimentation assay was developed to confirm these results.

Funding: NSF CHE-1852369

Program/mechanism supporting research/creative efforts: the WVU Chemistry REU (Brian Popp & Michelle Richards-Babb)