Huntington’s disease (HD) is a fatal neurodegenerative genetic disorder, deteriorating both the patient’s physical and mental abilities and ultimately resulting in death. There is currently no cure for the disease, only treatments to alleviate symptoms. HD is caused by huntingtin (htt) protein misfolding that results in oligomeric and fibrillar aggregates. The misfolding is the result of a genetic mutation that leads to an expanded polyglutamine (polyQ) domain near the N-terminus of htt. The htt polyQ region is flanked by a 17 amino acid N-terminal sequence (Nt17) and a proline-rich region, both of which play a role in the aggregation process. Nt17 interacts with cell membranes, resulting in an interest in understanding the htt binding mechanism and subsequent effects on both protein aggregation and membrane structure. Because abnormalities in lipid metabolism have been found in HD patients, it is important to understand the role of the membrane composition in this interaction. To provide mechanistic insight to protein-membrane binding and subsequent htt aggregation, two complementary techniques were used: circular dichroism (CD) to measure protein secondary structure and isothermal titration calorimetry (ITC) to quantify thermodynamic parameters. The cell membrane was modeled with large unilamellar vesicles (LUVs) composed of varying ratios of total brain lipid extract, zwitterionic phosphatidylcholine (PC), and negatively charged phosphatidylserine (PS) lipids. Nt17 membrane binding was monitored with CD by following the transition from solution phase random coil to interfacial alpha helical structures. The magnitude and kinetics of peptide binding correlate with the proportion of negatively charged lipid indicating the role of electrostatics and membrane composition in this interaction. Additionally, ITC data will be presented to provide insight to the enthalpy and htt-vesicle binding stoichiometry.<br/>

Measuring the interaction of polyglutamine peptides with lipid membranes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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