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Title: Investigating the Structural Impact of the Glutamine Repeat in Huntingtin Assembly

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.
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  1. ORNL
Publication Date:
OSTI Identifier:
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biophysical Journal; Journal Volume: 107; Journal Issue: 2
Research Org:
Oak Ridge National Laboratory (ORNL); High Flux Isotope Reactor (HFIR); Center for Structural Molecular Biology (CSMB)
Sponsoring Org:
SC USDOE - Office of Science (SC)
Country of Publication:
United States