Investigating the structural impact of the glutamine repeat in huntingtin assembly

Tatiana Perevozchikova; Christopher B. Stanley; Helen P. McWilliams-Koeppen; Erica L. Rowe; Valerie Berthelier

doi:10.1016/j.bpj.2014.06.002

Investigating the structural impact of the glutamine repeat in huntingtin assembly

Tatiana Perevozchikova, Christopher B. Stanley, Helen P. McWilliams-Koeppen, Erica L. Rowe, Valerie Berthelier

Scalable Biomedical Modeling

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Pages (from-to)	411-421
Number of pages	11
Journal	Biophysical Journal
Volume	107
Issue number	2
DOIs	https://doi.org/10.1016/j.bpj.2014.06.002
State	Published - Jul 15 2014

Funding

The experiments conducted at Oak Ridge National Laboratory’s Center for Structural Molecular Biology were supported by the Office of Biological and Environmental Research using facilities supported by the U.S. Department of Energy, managed by UT-Battelle, LLC under contract No. DE-AC05-00OR22725. This work was also supported in part by The Physicians’ Medical Education and Research Foundation (T.P.) and by NIH grant 1R21NS056325-01A1 (V.B.).

Funders	Funder number
Physicians’ Medical Education and Research Foundation
UT-Battelle, LLC
National Institutes of Health
U.S. Department of Energy
National Institute of Neurological Disorders and Stroke	R21NS056325

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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.",

author = "Tatiana Perevozchikova and Stanley, {Christopher B.} and McWilliams-Koeppen, {Helen P.} and Rowe, {Erica L.} and Valerie Berthelier",

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AU - Rowe, Erica L.

AU - Berthelier, Valerie

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Investigating the structural impact of the glutamine repeat in huntingtin assembly

Abstract

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