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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 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: Published Online
Status: Published
Schools: Biosciences
Uncontrolled Keywords: TDP-43, zinc, aggregation, amyotrophic lateral sclerosis
Publisher: Nature Publishing Group
ISSN: 2045-2322
Date of First Compliant Deposit: 30 June 2017
Date of Acceptance: 23 June 2017
Last Modified: 02 Jan 2018 12:18
URI: http://orca.cf.ac.uk/id/eprint/101965

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