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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...

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Autores principales: Ahmadi, Soha, Zhu, Shaolong, Sharma, Renu, Wu, Bing, Soong, Ronald, Dutta Majumdar, R., Wilson, Derek J., Simpson, Andre J., Kraatz, Heinz-Bernhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
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.
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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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