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. ORCID: https://orcid.org/0000-0001-8570-5648 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

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

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:	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:	05 May 2023 22:38
URI:	https://orca.cardiff.ac.uk/id/eprint/101965

Citation Data

Cited 35 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item