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bioRxiv · 10.1101/2023.07.21.549993

Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils from Huntington's disease

Bagherpoor Helabad, M.·Matlahov, I.·Daldrop, J. O.·Jain, G.·van der Wel, P. C. A.·Miettinen, M. S.
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Abstract

Neurodegeneration in Huntingtons disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinsons and Alzheimers diseases, the atomic-level structure of HTTex1 fibrils has remained unknown, limiting diagnostic and treatment efforts. We present and analyze the structure of fibrils formed by polyQ peptides and polyQ-expanded HTTex1 in vitro. Atomic-resolution perspectives are enabled by an integrative analysis and unrestrained all-atom molecular dynamics (MD) simulations incorporating experimental data from electron microscopy (EM), solid-state NMR, and other techniques. Alongside the use of prior data, we report new magic angle spinning NMR studies of glutamine residues of the polyQ fibril core and surface, distinguished via hydrogen-deuterium exchange (HDX). Our study provides a new understanding of the structure of the core as well as surface of aggregated HTTex1, including the fuzzy coat and polyQ-water interface. The obtained data are discussed in context of their implications for understanding the detection of such aggregates (diagnostics) as well as known biological properties of the fibrils.

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Bagherpoor Helabad, M., Matlahov, I., Daldrop, J. O., Jain, G., van der Wel, P. C. A., Miettinen, M. S.. 2023-07-21. Integrative determination of the atomic structure of mutant huntingtin exon 1 fibrils from Huntington's disease. https://doi.org/10.1101/2023.07.21.549993

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