Revealing the structural details of huntingtin fibrils using small-angle neutron scattering

Huntington's disease (HD) involves an abnormally expanded polyglutamine sequence in huntingtin (Htt) protein that makes it highly susceptible to aggregate. A current challenge is to map out the aggregation pathway by identifying the various precursor structures and establishing their roles in the disease. While it is highly suspected that the early oligomer species are responsible for toxicity, characterizing the end-state fibril structure is also a necessary step toward discovering the underlying mechanisms of early aggregate formation. We are actively investigating Htt structural kinetics and the resulting fibrils using small-angle neutron scattering (SANS). Here, we report on the characterization of fibrils from Htt-exon1-Q
₄₀
- a disease relevant Htt peptide as it contains a pathologically expanded glutamine repeat sequence and a proline-rich region. SANS on the end-state fibrils revealed structural similarities to the Perutz β-helixhollow cylinder model as opposed to the more commonly observed steric zipper structure found for many other amyloid fibrils. The structural details we have identified contribute toward elucidating the mechanism of pathological Htt assembly.