Abstract
In several neurodegenerative disorders, including Huntington’s disease (HD), aspects concerning the earliest of protein structures that form along the aggregation pathway have increasingly gained attention since these particular species are likely to be neurotoxic. We used time-resolved small-angle neutron scattering (SANS) to probe in solution these transient structures formed by peptides having the N-terminal sequence context of mutant huntingtin (Htt) exon 1. We obtained snapshots of the formed aggregates as the kinetic reaction ensued to yield quantitative information on their size and mass. At the early stage, small precursor species with an initial radius of gyration (Rg) of 16.1 ± 5.9 Å and average mass of a dimer to trimer were monitored. Structural growth was treated as two modes with a transition from three-dimensional early aggregate formation to two-dimensional fibril growth and association. Our SANS results on the internal structure of the mature fibrils demonstrate loose packing with about 1 peptide per 4.75 Å
β-sheet repeat distance, which is shown to be quantitatively consistent with a β-helix model. This research provides new insights into the structures forming along the pathway of Htt exon 1 aggregation and should assist in determining the role that precursors play in neuronal toxicity.
