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The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau
Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Ta...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581542/ https://www.ncbi.nlm.nih.gov/pubmed/34778381 http://dx.doi.org/10.3389/fmolb.2021.779240 |
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author | Lyu, Chen Da Vela, Stefano Al-Hilaly, Youssra Marshall, Karen E. Thorogate, Richard Svergun, Dmitri Serpell, Louise C. Pastore, Annalisa Hanger, Diane P. |
author_facet | Lyu, Chen Da Vela, Stefano Al-Hilaly, Youssra Marshall, Karen E. Thorogate, Richard Svergun, Dmitri Serpell, Louise C. Pastore, Annalisa Hanger, Diane P. |
author_sort | Lyu, Chen |
collection | PubMed |
description | Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. By using atomic force microscopy, circular dichroism, transmission electron microscopy and X-ray fiber diffraction, we provide evidence that Tau35 aggregation is mechanistically and morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies. |
format | Online Article Text |
id | pubmed-8581542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85815422021-11-12 The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau Lyu, Chen Da Vela, Stefano Al-Hilaly, Youssra Marshall, Karen E. Thorogate, Richard Svergun, Dmitri Serpell, Louise C. Pastore, Annalisa Hanger, Diane P. Front Mol Biosci Molecular Biosciences Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. By using atomic force microscopy, circular dichroism, transmission electron microscopy and X-ray fiber diffraction, we provide evidence that Tau35 aggregation is mechanistically and morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies. Frontiers Media S.A. 2021-10-28 /pmc/articles/PMC8581542/ /pubmed/34778381 http://dx.doi.org/10.3389/fmolb.2021.779240 Text en Copyright © 2021 Lyu, Da Vela, Al-Hilaly, Marshall, Thorogate, Svergun, Serpell, Pastore and Hanger. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Lyu, Chen Da Vela, Stefano Al-Hilaly, Youssra Marshall, Karen E. Thorogate, Richard Svergun, Dmitri Serpell, Louise C. Pastore, Annalisa Hanger, Diane P. The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title_full | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title_fullStr | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title_full_unstemmed | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title_short | The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau |
title_sort | disease associated tau35 fragment has an increased propensity to aggregate compared to full-length tau |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581542/ https://www.ncbi.nlm.nih.gov/pubmed/34778381 http://dx.doi.org/10.3389/fmolb.2021.779240 |
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