INVESTIGATING AGGREGATION AND PEPTIDE-LIPID INTERACTIONS IN HUNTINGTON’S DISEASE

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by the abnormal expansion of a polyglutamine (polyQ) tract within the huntingtin (htt) protein. This expansion leads to cognitive decline, motor dysfunction, and psychiatric symptoms. Research has primarily focused on the htt exon 1 (httex1) fragment, as each of its domains contributes uniquely to disease pathology. In this thesis, we investigate two distinct but related questions using the httex1 protein system: (1) how membrane curvature and composition modulate the membrane-binding behavior of Nt17, the amphipathic N-terminal domain; and (2) how polyQ length influences the aggregation and structural properties of Nt17+polyQ oligomers. Experimental progress on htt has been hindered by the flexible and heterogeneous nature of polyQ-containing proteins. To overcome these limitations, we employ coarse-grained molecular dynamics (CG-MD) simulations, which allow access to large spatiotemporal scales and mechanistic detail. The first chapter provides a comprehensive review of the current understanding of htt structure, aggregation, and membrane interactions, highlighting key open questions. Chapter 2 focuses on structural differences between oligomers of wild-type htt and its mutant forms (polyQ ≥ 36), revealing that mutant oligomers exhibit greater structural polymorphism and expose hydrophobic residues on its periphery. Chapters 3 and 4 shift focus to the membrane-binding behavior of the Nt17 domain. In Chapter 3, we demonstrate that Nt17 preferentially partitions into curved membrane regions using a planar–hemispherical membrane system, suggesting a role for curvature sensing in subcellular localization. Chapter 4 explores how membrane surface charge influences Nt17 binding. The addition of anionic lipids increases overall membrane association and reveals a delicate balance between electrostatic attraction and hydrophobic insertion. We hypothesize that increasing anionic lipid content beyond a threshold may diminish curvature sensitivity by saturating electrostatic interactions. The final chapter synthesizes these findings and outlines future computational directions. Taken together, this work suggests a mechanistic basis for the enhanced aggregation and membrane association observed in HD. Specifically, wild-type oligomers form compact hydrophobic cores whereas mutant oligomers expose hydrophobic residues like phenylalanine at their periphery, suggesting differing methods of partitioning to the membranes. These differences potentially contribute to downstream cellular dysfunction in HD.