Investigating the Structural Impact of the Glutamine Repeat in Huntingtin Assembly

Journal Article · Wed Jan 01 04:00:00 EST 2014 · Biophysical Journal

DOI:https://doi.org/10.1016/j.bpj.2014.06.002· OSTI ID:1147690

Perevozchikova, Tatiana ^[1]; Stanley, Christopher B ^[1]; McWilliams-Koeppen, Helen P ^[1]; Rowe, Erica L ^[1]; Berthelier-Jung, Valerie M ^[1]

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1. ORNL

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 pack- ing arrangement consistent with the common amyloid sterical zipper model, whereas NtQ42P10 fibrils present a better fit to the Perutz b-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.

• Research Organization: Oak Ridge National Laboratory (ORNL); High Flux Isotope Reactor (HFIR); Center for Structural Molecular Biology (CSMB)
• Sponsoring Organization: SC USDOE - Office of Science (SC)
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 1147690
• Journal Information: Biophysical Journal, Journal Name: Biophysical Journal Journal Issue: 2 Vol. 107; ISSN 0006-3495
• Country of Publication: United States
• Language: English