Huntingtin Aggregation Is Modified in the Presence of a Variety of Lipid Membranes

Abstract

Huntington's Disease is a fatal neurodegenerative disorder characterized by an expanded polyglutamine (polyQ) region of the huntingtin protein (htt) that leads to the formation of toxic aggregates. The first 17 amino-terminal residues of htt (Nt17) have been shown to promote this oligomer formation, and also comprise a lipid binding domain. The subcellular localization and interaction of htt containing expanded polyQ domains with membranous surfaces has been well documented and suggests that these interactions play a role in HD pathogenesis. While protein/lipid membrane interactions play an important role in a number of amyloid-related diseases, the protein represents only one of the participants. For example, the size and charge of the lipid headgroups likely influence the interaction between Nt17 and lipid membranes. Any effect on lipid binding would also affect the aggregation and trafficking of htt. Determining factors that regulate the affinity of htt for membranes could not only help understand the normal functions of htt, but could lead to a better understanding of how to modify protein-lipid interaction for therapeutic purposes. As a result, we undertook a series of experiments to determine the role of specific lipids in modulating the htt/lipid interaction and resulting aggregation. Htt aggregation in the presence of POPC, DOPC, DMPC, POPG, POPE, POPS, and total brain lipid extract were investigated via thioflavin T aggregation assays and other biochemical assays. In addition, the modulating effect of cholesterol was also explored.