title: Investigating the structural impact of the glutamine repeat in huntingtin assembly.
abstract: Acquiring detailed structural information about the various aggregation states of the huntingtin-exon1 protein (Htt-exon1) is crucial not only for identifying the true nature of the neurotoxic species responsible for Huntington's disease (HD) but also for designing effective therapeutics. Using time-resolved small-angle neutron scattering (TR-SANS), we followed the conformational changes that occurred during fibrillization of the pathologic form of Htt-exon1 (NtQ42P10) and compared the results with those obtained for the wild-type (NtQ22P10). Our results show that the aggregation pathway of NtQ22P10 is very different from that of NtQ42P10, as the initial steps require a monomer to 7-mer transition stage. In contrast, the earliest species identified for NtQ42P10 are monomer and dimer. The divergent pathways ultimately result in NtQ22P10 fibrils that possess a packing arrangement consistent with the common amyloid sterical zipper model, whereas NtQ42P10 fibrils present a better fit to the Perutz β-helix structural model. The structural details obtained by TR-SANS should help to delineate the key mechanisms that underpin Htt-exon1 aggregation leading to HD.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center-Graduate School of Medicine, Knoxville, Tennessee.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Perevozchikova
authors.affiliation: Biology and Biomedical Sciences Group, Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee. Electronic address: stanleycb@ornl.gov.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Stanley
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center-Graduate School of Medicine, Knoxville, Tennessee.
authors.forename: Helen P
authors.initials: HP
authors.lastname: McWilliams-Koeppen
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center-Graduate School of Medicine, Knoxville, Tennessee.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Rowe
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center-Graduate School of Medicine, Knoxville, Tennessee. Electronic address: vberthel@utmck.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Berthelier
mesh_terms: D005091:Exons; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D033363:Neutron Diffraction; D010455:Peptides / Q000737:chemistry*; D066263:Protein Aggregation, Pathological; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle
chemical_list: D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine