title: Structural formation of huntingtin exon 1 aggregates probed by small-angle neutron scattering.
abstract: In several neurodegenerative disorders, including Huntington's disease, aspects concerning the earliest of protein structures that form along the aggregation pathway have increasingly gained attention because these particular species are likely to be neurotoxic. We used time-resolved small-angle neutron scattering to probe in solution these transient structures formed by peptides having the N-terminal sequence context of mutant huntingtin 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 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 small-angle neutron scattering results on the internal structure of the mature fibrils demonstrate loose packing with ~1 peptide per 4.75 Åβ-sheet repeat distance, which is shown to be quantitatively consistent with a β-helix model. This research provides what we believe to be new insights into the structures forming along the pathway of huntingtin exon 1 aggregation and should assist in determining the role that precursors play in neuronal toxicity.
authors.affiliation: Neutron Scattering Science Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA. stanleycb@ornl.gov
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Stanley
authors.forename: Tatiana
authors.initials: T
authors.lastname: Perevozchikova
authors.forename: Valerie
authors.initials: V
authors.lastname: Berthelier
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000648:ultrastructure; D005091:Exons / Q000235:genetics*; D005973:Glutamine / Q000737:chemistry; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D033363:Neutron Diffraction / Q000379:methods*; D020836:Protein Structure, Quaternary; D053838:Scattering, Small Angle; D013997:Time Factors
chemical_list: D000682:Amyloid; D009419:Nerve Tissue Proteins; D005973:Glutamine