Unraveling the Polyglutamine Aggregation Pathway in Huntington's Disease by Small-Angle Neutron Scattering

Abstract

The presence of an abnormally expanded polyglutamine (polyGln) sequence in huntingtin protein ultimately results in beta-sheet-rich fibrillar aggregates, a hallmark of Huntington's disease. Current challenges are to map out the polyGln aggregation pathway by identifying the various precursor structures and establish their pathological roles. We are using time-resolved small-angle neutron scattering (SANS) to probe the aggregates formed by peptides having the protein context of huntingtin exon 1 (HD protein) and with varying polyGln lengths. SANS is a particularly useful technique for following structural changes on the nanometer length-scale in solution. From the time-resolved scattering data, we obtain snapshots of the polyGln structures as the kinetics reaction ensues, which yields quantitative information on the size and shape of precursors and the internal structure of the resulting fibrils. Measured changes in the radius of gyration and mass per length illustrate multiple growth regimes with a transition from early aggregates to fibril elongation and association. Our SANS results on mature polyGln fibrils are consistent with the Perutz beta-helix structural model. This research is providing new insights into the pathway of polyGln aggregation and should later assist in determining the role that precursors play in neuronal toxicity.