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Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease
Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919914/ https://www.ncbi.nlm.nih.gov/pubmed/27070645 http://dx.doi.org/10.3390/biom6020019 |
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author | Lai, Robert Y. K. Harrington, Charles R. Wischik, Claude M. |
author_facet | Lai, Robert Y. K. Harrington, Charles R. Wischik, Claude M. |
author_sort | Lai, Robert Y. K. |
collection | PubMed |
description | Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. |
format | Online Article Text |
id | pubmed-4919914 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-49199142016-06-24 Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease Lai, Robert Y. K. Harrington, Charles R. Wischik, Claude M. Biomolecules Article Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. MDPI 2016-04-08 /pmc/articles/PMC4919914/ /pubmed/27070645 http://dx.doi.org/10.3390/biom6020019 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lai, Robert Y. K. Harrington, Charles R. Wischik, Claude M. Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title | Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title_full | Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title_fullStr | Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title_full_unstemmed | Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title_short | Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease |
title_sort | absence of a role for phosphorylation in the tau pathology of alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919914/ https://www.ncbi.nlm.nih.gov/pubmed/27070645 http://dx.doi.org/10.3390/biom6020019 |
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