Inhibition of huntingtin aggregation by its N-terminal 17-residue peptide and its analogs

The N-terminal 17-residue stretch of huntingtin (htt^N17) folds into an amphipathic α-helix. The htt^N17-harboring polyQ peptides form oligomers that are mediated via the assembly of the htt^N17 α-helices. The oligomerization results in higher local concentration of the polyglutamine (polyQ) region, thereby facilitating amyloid formation. The htt^N17 co-assembles with the htt^N17-harbouring polyQ peptides, thereby reducing the local polyQ concentration, and consequently inhibiting aggregation. This study presents the aggregation inhibition of the exon I region of pathogenic huntingtin by htt^N17 and its analogs. The C-terminal amidation of htt^N17 is found to be essential for activity. The htt^N17 peptides with free amino terminus and the acetylated amino terminus possess comparable activity. The htt^N17 analog, wherein the Leu7 and Ala10 are substituted with 2-aminoisobutyric acid residues, exhibits significantly higher activity than the native htt^N17.