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Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids

Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer’s disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the...

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Autores principales: KrishnaKumar, V. Guru, Paul, Ashim, Gazit, Ehud, Segal, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758761/
https://www.ncbi.nlm.nih.gov/pubmed/29311706
http://dx.doi.org/10.1038/s41598-017-18443-2
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author KrishnaKumar, V. Guru
Paul, Ashim
Gazit, Ehud
Segal, Daniel
author_facet KrishnaKumar, V. Guru
Paul, Ashim
Gazit, Ehud
Segal, Daniel
author_sort KrishnaKumar, V. Guru
collection PubMed
description Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer’s disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment.
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spelling pubmed-57587612018-01-10 Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids KrishnaKumar, V. Guru Paul, Ashim Gazit, Ehud Segal, Daniel Sci Rep Article Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer’s disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment. Nature Publishing Group UK 2018-01-08 /pmc/articles/PMC5758761/ /pubmed/29311706 http://dx.doi.org/10.1038/s41598-017-18443-2 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
KrishnaKumar, V. Guru
Paul, Ashim
Gazit, Ehud
Segal, Daniel
Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title_full Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title_fullStr Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title_full_unstemmed Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title_short Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids
title_sort mechanistic insights into remodeled tau-derived phf6 peptide fibrils by naphthoquinone-tryptophan hybrids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758761/
https://www.ncbi.nlm.nih.gov/pubmed/29311706
http://dx.doi.org/10.1038/s41598-017-18443-2
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