Lipid headgroups alter huntingtin aggregation on membranes

Huntington's Disease is a fatal neurodegenerative disorder caused by expansion of a glutamine repeat region (polyQ) beyond a critical threshold within exon1 of the huntingtin protein (htt). As a consequence of polyQ expansion, htt associates into a variety of aggregate species that are thought to underlie cellular toxicity. Within cells, htt associates with numerous membranous organelles and surfaces that exert influence on the aggregation process. In particular, the first 17 amino acids at the N-terminus of htt (Nt17) serve as a lipid-binding domain that is intrinsically disordered in bulk solution but adopts an amphipathic a-helical structure upon binding membranes. Beyond this, Nt17 is implicated in initiating htt fibrillization. As the interaction between Nt17 and lipid membranes is likely influenced by lipid properties, the impact of lipid headgroups on htt-exon1 aggregation, membrane activity, and the ability to form protein:lipid complexes was determined. Htt-exon1 with a disease-length polyQ domain (46Q) was exposed to lipid vesicles comprised of lipids with either zwitterionic (POPC and POPE) or anionic (POPG and POPS) headgroups. With zwitterionic head groups, large lipid to peptide ratios were required to have a statistically significant impact on htt aggregation. Anionic lipids enhanced htt fibrillization, even at low lipid:protein ratios, and this was accompanied by changes in aggregate morphology. Despite the larger impact of anionic lipids, htt-exon1(46Q) was more membrane active with zwitterionic lipid systems. The ability of Nt17 to form complexes with lipids was also mediated by lipid headgroups as zwitterionic ionic lipids more readily associated with multimeric forms of Nt17 in comparison with anionic lipids. Collectively, these results highlight the complexity of htt/membrane interactions and the resulting impact on the aggregation process.

Automated summary

The interaction between lipid headgroups and htt-exon1 aggregation was investigated, with anionic lipids enhancing fibrillization and zwitterionic lipids affecting membrane activity. Nt17 was found to more readily form complexes with zwitterionic lipids compared to anionic lipids, showcasing the complexity of htt/membrane interactions.