Célia Rabhi, Nicolas Babault, Céline Martin, Bénédicte Desforges, Alexandre Maucuer, Vandana Joshi, Serhii Pankivskyi, Yitian Feng, Guillaume Bollot, Revital Rattenbach, David Pastré, Ahmed Bouhss
Communications biology 2025 Jan 28Protein 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).
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
PMID: 39875548
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