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

Garnier, Cyrille, Devred, Francois, Byrne, Deborah, Puppo, Remy, Roman, Andrei Yu., Malesinski, Soazig, Golovin, Andrey V., Lebrun, Regine, Ninkina, Natalia N. and Tsvetkov, Philipp O. 2017. Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates. Scientific Reports 7 , 6812. 10.1038/s41598-017-07215-7

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Uncontrolled Keywords: TDP-43, zinc, aggregation, amyotrophic lateral sclerosis
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Publishing Group
ISSN: 2045-2322
Date of First Compliant Deposit: 30 June 2017
Date of Acceptance: 23 June 2017
Last Modified: 03 Jun 2020 12:30
URI: http://orca.cf.ac.uk/id/eprint/101965

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