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

Huntington's disease is a neurodegenerative dis-order caused by an expanded polyglutamine (polyQ) domainwithin the huntingtin protein (htt) that initiates toxic proteinaggregation. Htt directly interacts with membranes, influencingaggregation and spurring membrane abnormalities. Theseinteractions are facilitated by the 17 N-terminal residues (Nt17)that form an amphipathic alpha-helix implicated in both lipid bindingand aggregation. Here, the impact of unsaturation in phospholipidtails on htt-lipid interaction and htt aggregation was determined.There was no correlation between the degree of htt-lipidcomplexation and the degree of htt aggregation in the presenceof each lipid system, indicating that lipid systems with differentproperties uniquely alter the membrane-mediated aggregationmechanisms. Also, the association between Nt17 and membrane surfaces is determined by complementarity between hydrophobicresidues and membrane defects and how easily the peptide can partition into the bilayer. Our results provide critical insights intohow membrane physical properties influence downstream htt aggregation