{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Zurich"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "M. Polymenidou"
    },
    {
      "name": "A. Zbinden"
    },
    {
      "name": "I. Smok"
    },
    {
      "name": "F. Pellegrini"
    },
    {
      "name": "A. Oertel"
    },
    {
      "name": "A. Clery"
    },
    {
      "name": "V. I. Wiersma"
    },
    {
      "name": "W.-P. Huang"
    },
    {
      "name": "B. Gatta"
    },
    {
      "name": "W. Zhong"
    },
    {
      "name": "Y. Li"
    },
    {
      "name": "M. Götze"
    },
    {
      "name": "M. Peter"
    },
    {
      "name": "N. Bargenda"
    },
    {
      "name": "M. Hruska-Plochan"
    },
    {
      "name": "A. Caflisch"
    },
    {
      "name": "P. Fratta"
    },
    {
      "name": "T. Shelkovnikova"
    },
    {
      "name": "F. H.- T. Allain"
    },
    {
      "name": "A. Leitner"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dq38wydmaqpa0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.01.755875",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1.full",
  "id": "dq38wydmaqpa0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "molecular biology"
    ],
    [
      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7220474644",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dq38wydmaqpa0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:03Z",
      "native_id": "10.64898/2026.10.01.755875",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.755875v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion",
  "title_text": "Monomeric TDP-43 binds GU-rich RNA via its NTD but only its oligomers block cryptic exon inclusion",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:03Z",
  "url": "https://research.draconitic.com/paper/dq38wydmaqpa0",
  "venue": "bioRxiv",
  "versions": []
}