Physicochemical Properties Altered by the Tail Group of Lipid Membranes Influence Huntingtin Aggregation and Lipid Binding.

Abstract

Huntington's disease is a neurodegenerative disorder caused by an expanded polyglutamine (polyQ) domain within the huntingtin protein (htt) that initiates toxic protein aggregation. Htt directly interacts with membranes, influencing aggregation and spurring membrane abnormalities. These interactions are facilitated by the 17 N-terminal residues (Nt17) that form an amphipathic α-helix implicated in both lipid binding and aggregation. Here, the impact of unsaturation in phospholipid tails on htt-lipid interaction and htt aggregation was determined. There was no correlation between the degree of htt-lipid complexation and the degree of htt aggregation in the presence of each lipid system, indicating that lipid systems with different properties uniquely alter the membrane-mediated aggregation mechanisms. Also, the association between Nt17 and membrane surfaces is determined by complementarity between hydrophobic residues and membrane defects and how easily the peptide can partition into the bilayer. Our results provide critical insights into how membrane physical properties influence downstream htt aggregation.