Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion

Abstract

TDP-43 aggregation is a pathological feature of several neurodegenerative diseases, resulting in nuclear loss of function and RNA dysregulation, including cryptic exon derepression. TDP-43 comprises two RNA recognition motifs required for canonical RNA binding, a low-complexity domain implicated in phase separation, and an N-terminal domain (NTD) that mediates oligomerization. While NTD-driven oligomerization is critical for TDP-43 splicing function, some studies suggest a direct interaction of NTD with RNA. Here, we investigated RNA binding by the NTD and its functional interplay with oligomerization. We show that the NTD preferentially binds UG-rich RNA via residues located at the oligomerization interface. The NTD engaged RNA only on monomeric TDP-43, as RNA binding and oligomerization compete for the same interface and rely on similar interaction modes. By disentangling these competing activities, we demonstrated that oligomerization, but not NTD-RNA interaction, is essential for TDP-43-dependent alternative splicing and repression of cryptic exons. Our findings uncover a previously unappreciated RNA-binding activity within the TDP-43 NTD that directly competes with oligomerization and establish oligomerization as a key determinant of TDP-43 cryptic exon repression.

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BibTeX

@misc{polymenidou2026monomeric,
  title = {{Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion}},
  author = {M. Polymenidou and A. Zbinden and I. Smok and F. Pellegrini and A. Oertel and A. Clery and V. I. Wiersma and W.-P. Huang and B. Gatta and W. Zhong and Y. Li and M. Götze and M. Peter and N. Bargenda and M. Hruska-Plochan and A. Caflisch and P. Fratta and T. Shelkovnikova and F. H.- T. Allain and A. Leitner},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.01.755875},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion
AU  - M. Polymenidou
AU  - A. Zbinden
AU  - I. Smok
AU  - F. Pellegrini
AU  - A. Oertel
AU  - A. Clery
AU  - V. I. Wiersma
AU  - W.-P. Huang
AU  - B. Gatta
AU  - W. Zhong
AU  - Y. Li
AU  - M. Götze
AU  - M. Peter
AU  - N. Bargenda
AU  - M. Hruska-Plochan
AU  - A. Caflisch
AU  - P. Fratta
AU  - T. Shelkovnikova
AU  - F. H.- T. Allain
AU  - A. Leitner
PY  - 2026
DA  - 2026/10/01
PB  - bioRxiv
DO  - 10.64898/2026.10.01.755875
UR  - https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1
AB  - TDP-43 aggregation is a pathological feature of several neurodegenerative diseases, resulting in nuclear loss of function and RNA dysregulation, including cryptic exon derepression. TDP-43 comprises two RNA recognition motifs required for canonical RNA binding, a low-complexity domain implicated in phase separation, and an N-terminal domain (NTD) that mediates oligomerization. While NTD-driven oligomerization is critical for TDP-43 splicing function, some studies suggest a direct interaction of NTD with RNA. Here, we investigated RNA binding by the NTD and its functional interplay with oligomerization. We show that the NTD preferentially binds UG-rich RNA via residues located at the oligomerization interface. The NTD engaged RNA only on monomeric TDP-43, as RNA binding and oligomerization compete for the same interface and rely on similar interaction modes. By disentangling these competing activities, we demonstrated that oligomerization, but not NTD-RNA interaction, is essential for TDP-43-dependent alternative splicing and repression of cryptic exons. Our findings uncover a previously unappreciated RNA-binding activity within the TDP-43 NTD that directly competes with oligomerization and establish oligomerization as a key determinant of TDP-43 cryptic exon repression.
ER  -

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