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The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation

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Rengifo-Gonzalez, Juan Carlos | El Hage, Krystel | Clément, Marie-Jeanne | Steiner, Emilie | Joshi, Vandana | Craveur, Pierrick | Durand, Dominique | Pastré, David | Bouhss, Ahmed

Edité par CCSD ; eLife Sciences Publication -

International audience. 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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