Academic Journal
Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates
| Title: | Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates |
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| Authors: | Cyrille Garnier, François Devred, Deborah Byrne, Rémy Puppo, Andrei Yu. Roman, Soazig Malesinski, Andrey V. Golovin, Régine Lebrun, Natalia N. Ninkina, Philipp O. Tsvetkov |
| Source: | Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
| Publisher Information: | Nature Portfolio, 2017. |
| Publication Year: | 2017 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Medicine, Science |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-017-07215-7 |
| Access URL: | https://doaj.org/article/2c0c8563f1e940049ce56f22e73b5816 |
| Accession Number: | edsdoj.2c0c8563f1e940049ce56f22e73b5816 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 20452322 |
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| DOI: | 10.1038/s41598-017-07215-7 |
| Published in: | Scientific Reports |
| Language: | English |