TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm
Abstract 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 cy...
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07456-7 |
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| author | Célia Rabhi Nicolas Babault Céline Martin Bénédicte Desforges Alexandre Maucuer Vandana Joshi Serhii Pankivskyi Yitian Feng Guillaume Bollot Revital Rattenbach David Pastré Ahmed Bouhss |
| author_facet | Célia Rabhi Nicolas Babault Céline Martin Bénédicte Desforges Alexandre Maucuer Vandana Joshi Serhii Pankivskyi Yitian Feng Guillaume Bollot Revital Rattenbach David Pastré Ahmed Bouhss |
| author_sort | Célia Rabhi |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-d51ab7f245b8462b868f2dcd0deaa076 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-d51ab7f245b8462b868f2dcd0deaa0762025-02-02T12:37:29ZengNature PortfolioCommunications Biology2399-36422025-01-018111810.1038/s42003-025-07456-7TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasmCélia Rabhi0Nicolas Babault1Céline Martin2Bénédicte Desforges3Alexandre Maucuer4Vandana Joshi5Serhii Pankivskyi6Yitian Feng7Guillaume Bollot8Revital Rattenbach9David Pastré10Ahmed Bouhss11Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)SYNSIGHT4P-PharmaUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)SYNSIGHT4P-PharmaUniversité Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Université Paris-Saclay, INSERM U1204, Univ Evry, Structure-Activité des Biomolécules Normales et Pathologiques (SABNP)Abstract 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.https://doi.org/10.1038/s42003-025-07456-7 |
| spellingShingle | 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 |
| title | TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm |
| title_full | TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm |
| title_fullStr | TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm |
| title_full_unstemmed | TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm |
| title_short | TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm |
| title_sort | tdp 43 nuclear retention is antagonized by hypo phosphorylation of its c terminus in the cytoplasm |
| url | https://doi.org/10.1038/s42003-025-07456-7 |
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