Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion
Year: 2026
Type: preprint
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.
Authors: Aurélie Zbinden, Izabela Smok, Flaminia Pellegrini, Alexandra Oertel, Antoine Cléry, Vera I. Wiersma, Wan-Ping Huang, Beatrice Gatta, Weijia Zhong, Yaozong Li, Michael Götze, Martina Peter, Niklas Bargenda, Marian Hruska-Plochan, Amedeo Caflisch, Pietro Fratta, Tatyana A. Shelkovnikova, Frédéric Allain, Alexander Leitner, Magdalini Polymenidou
Institutions: University of Zurich, The Francis Crick Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, ETH Zurich, Institute for Molecular Systems Biology, Institute of Biochemistry, Amsterdam University Medical Centers, University of Sheffield
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mechanistic studies of ALS-causative mutations and RNP-focussed drug discovery using in vitro reconstitution of RNP complexes, RNA-protein complexes in health and disease and their therapeutic targeting, NCCR RNA & disease: The role of RNA biology in disease mechanisms, NCCR RNA & disease: The role of RNA biology in disease mechanisms, G7780817649, G880118091
OpenAlex ID: W7220474644