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Aggregation of Microtubule Binding Repeats of Tau Protein is Promoted by Cu(2+)
[Image: see text] Understanding the factors that give rise to tau aggregation and reactive oxygen species (ROS) is the key aspect in Alzheimer’s disease pathogenesis. Microtubule (MT) binding repeats of tau protein were suggested to play a critical role in tau aggregation. Here, we show that the int...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463671/ https://www.ncbi.nlm.nih.gov/pubmed/31001602 http://dx.doi.org/10.1021/acsomega.8b03595 |
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author | Ahmadi, Soha Zhu, Shaolong Sharma, Renu Wu, Bing Soong, Ronald Dutta Majumdar, R. Wilson, Derek J. Simpson, Andre J. Kraatz, Heinz-Bernhard |
author_facet | Ahmadi, Soha Zhu, Shaolong Sharma, Renu Wu, Bing Soong, Ronald Dutta Majumdar, R. Wilson, Derek J. Simpson, Andre J. Kraatz, Heinz-Bernhard |
author_sort | Ahmadi, Soha |
collection | PubMed |
description | [Image: see text] Understanding the factors that give rise to tau aggregation and reactive oxygen species (ROS) is the key aspect in Alzheimer’s disease pathogenesis. Microtubule (MT) binding repeats of tau protein were suggested to play a critical role in tau aggregation. Here, we show that the interaction of Cu(2+) with full-length MT binding repeats R1–R4 leads to the aggregation, and a Cys-based redox chemistry is critically involved in tau aggregation leading to disulfide-bridge dimerization of R2 and R3 and further aggregation into a fibrillar structure. Notably, ascorbate and glutathione, the most abundant antioxidants in neurons, cannot prevent the effect of Cu(2+) on R2 and R3 aggregation. Detailed ESI-MS and NMR experiments demonstrate the interaction of Cu(2+) with MT binding repeats. We show that redox activity of copper increases when bound to the MT repeats leading to ROS formation, which significantly contribute to cellular damage and neuron death. Results presented here provide new insights into the molecular mechanism of tau aggregation and ROS formation and suggest a new target domain for tau aggregation inhibitors. |
format | Online Article Text |
id | pubmed-6463671 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-64636712019-04-16 Aggregation of Microtubule Binding Repeats of Tau Protein is Promoted by Cu(2+) Ahmadi, Soha Zhu, Shaolong Sharma, Renu Wu, Bing Soong, Ronald Dutta Majumdar, R. Wilson, Derek J. Simpson, Andre J. Kraatz, Heinz-Bernhard ACS Omega [Image: see text] Understanding the factors that give rise to tau aggregation and reactive oxygen species (ROS) is the key aspect in Alzheimer’s disease pathogenesis. Microtubule (MT) binding repeats of tau protein were suggested to play a critical role in tau aggregation. Here, we show that the interaction of Cu(2+) with full-length MT binding repeats R1–R4 leads to the aggregation, and a Cys-based redox chemistry is critically involved in tau aggregation leading to disulfide-bridge dimerization of R2 and R3 and further aggregation into a fibrillar structure. Notably, ascorbate and glutathione, the most abundant antioxidants in neurons, cannot prevent the effect of Cu(2+) on R2 and R3 aggregation. Detailed ESI-MS and NMR experiments demonstrate the interaction of Cu(2+) with MT binding repeats. We show that redox activity of copper increases when bound to the MT repeats leading to ROS formation, which significantly contribute to cellular damage and neuron death. Results presented here provide new insights into the molecular mechanism of tau aggregation and ROS formation and suggest a new target domain for tau aggregation inhibitors. American Chemical Society 2019-03-15 /pmc/articles/PMC6463671/ /pubmed/31001602 http://dx.doi.org/10.1021/acsomega.8b03595 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Ahmadi, Soha Zhu, Shaolong Sharma, Renu Wu, Bing Soong, Ronald Dutta Majumdar, R. Wilson, Derek J. Simpson, Andre J. Kraatz, Heinz-Bernhard Aggregation of Microtubule Binding Repeats of Tau Protein is Promoted by Cu(2+) |
title | Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu(2+) |
title_full | Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu(2+) |
title_fullStr | Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu(2+) |
title_full_unstemmed | Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu(2+) |
title_short | Aggregation of Microtubule Binding Repeats of Tau
Protein is Promoted by Cu(2+) |
title_sort | aggregation of microtubule binding repeats of tau
protein is promoted by cu(2+) |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463671/ https://www.ncbi.nlm.nih.gov/pubmed/31001602 http://dx.doi.org/10.1021/acsomega.8b03595 |
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