The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
- Université Paris-Saclay, INSERM U1204, Univ Evry, France
- SYNSIGHT, France
- Université Paris-Saclay, CEA, CNRS, France
Abstract
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA Recognition Motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Genopole (SATURNE 2018-SABNP)
- Ahmed Bouhss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Rengifo-Gonzalez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
eLife 10:e67605.
https://doi.org/10.7554/eLife.67605
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