Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Abstract Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases....

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Autores principales:	Cyrille Garnier, François Devred, Deborah Byrne, Rémy Puppo, Andrei Yu. Roman, Soazig Malesinski, Andrey V. Golovin, Régine Lebrun, Natalia N. Ninkina, Philipp O. Tsvetkov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c0c8563f1e940049ce56f22e73b5816
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spelling	oai:doaj.org-article:2c0c8563f1e940049ce56f22e73b58162021-12-02T16:06:05ZZinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates10.1038/s41598-017-07215-72045-2322https://doaj.org/article/2c0c8563f1e940049ce56f22e73b58162017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07215-7https://doaj.org/toc/2045-2322Abstract Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases. Recently it was shown that zinc ions can provoke the aggregation of endogenous TDP-43 in cells, allowing to assume a direct interaction of TDP-43 with zinc ions. In this work, we investigated zinc binding to the 102–269 TDP-43 fragment, which comprise the two RNA recognition motifs. Using isothermal titration calorimetry, mass spectrometry, and differential scanning fluorimetry, we showed that zinc binds to this TDP-43 domain with a dissociation constant in the micromolar range and modifies its tertiary structure leading to a decrease of its thermostability. Moreover, the study by dynamic light scattering and negative stain electron microscopy demonstrated that zinc ions induce auto-association process of this TDP-43 fragment into rope-like structures. These structures are thioflavin-T-positive allowing to hypothesize the direct implication of zinc ions in pathological aggregation of TDP-43.Cyrille GarnierFrançois DevredDeborah ByrneRémy PuppoAndrei Yu. RomanSoazig MalesinskiAndrey V. GolovinRégine LebrunNatalia N. NinkinaPhilipp O. TsvetkovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cyrille Garnier François Devred Deborah Byrne Rémy Puppo Andrei Yu. Roman Soazig Malesinski Andrey V. Golovin Régine Lebrun Natalia N. Ninkina Philipp O. Tsvetkov Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
description	Abstract Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases. Recently it was shown that zinc ions can provoke the aggregation of endogenous TDP-43 in cells, allowing to assume a direct interaction of TDP-43 with zinc ions. In this work, we investigated zinc binding to the 102–269 TDP-43 fragment, which comprise the two RNA recognition motifs. Using isothermal titration calorimetry, mass spectrometry, and differential scanning fluorimetry, we showed that zinc binds to this TDP-43 domain with a dissociation constant in the micromolar range and modifies its tertiary structure leading to a decrease of its thermostability. Moreover, the study by dynamic light scattering and negative stain electron microscopy demonstrated that zinc ions induce auto-association process of this TDP-43 fragment into rope-like structures. These structures are thioflavin-T-positive allowing to hypothesize the direct implication of zinc ions in pathological aggregation of TDP-43.
format	article
author	Cyrille Garnier François Devred Deborah Byrne Rémy Puppo Andrei Yu. Roman Soazig Malesinski Andrey V. Golovin Régine Lebrun Natalia N. Ninkina Philipp O. Tsvetkov
author_facet	Cyrille Garnier François Devred Deborah Byrne Rémy Puppo Andrei Yu. Roman Soazig Malesinski Andrey V. Golovin Régine Lebrun Natalia N. Ninkina Philipp O. Tsvetkov
author_sort	Cyrille Garnier
title	Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
title_short	Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
title_full	Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
title_fullStr	Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
title_full_unstemmed	Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
title_sort	zinc binding to rna recognition motif of tdp-43 induces the formation of amyloid-like aggregates
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2c0c8563f1e940049ce56f22e73b5816
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Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

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