TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, a nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed a robust and automated method to assess protein self-assembly in the cytoplasm using microtubules as nanoplatforms. Importantly, we have analyzed specifically the self-assembly of full-length TDP-43 and its mRNA binding that are regulated by the phosphorylation of its self-adhesive C-terminus, which is the recipient of many pathological mutations. We show that C-terminus phosphorylation prevents the recruitment of TDP-43 in mRNA-rich stress granules only under acute stress conditions because of a low affinity for mRNA but not under mild stress conditions. In addition, the self-assembly of the C-terminus is negatively regulated by phosphorylation in the cytoplasm which in turn promotes TDP-43 nuclear import. We anticipate that reducing TDP-43 C-terminus self-assembly in the cytoplasm may be an interesting strategy to reverse TDP-43 nuclear depletion in neurodegenerative diseases. © 2025. The Author(s).

Citation

Célia Rabhi, Nicolas Babault, Céline Martin, Bénédicte Desforges, Alexandre Maucuer, Vandana Joshi, Serhii Pankivskyi, Yitian Feng, Guillaume Bollot, Revital Rattenbach, David Pastré, Ahmed Bouhss. TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm. Communications biology. 2025 Jan 28;8(1):136

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PMID: 39875548

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