The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity

  • Structure. 2025 May 27:S0969-2126(25)00184-4. doi: 10.1016/j.str.2025.05.006.
Emily G Oldani  1 ,  Kevin M Reynolds Caicedo  2 ,  McKenna E Spaeth Herda  2 ,  Adam H Sachs  2 ,  Erich G Chapman  3 ,  Sunil Kumar  4 ,  Daniel A Linseman  5 ,  Scott Horowitz  6
Affiliations
  • 1. Department of Chemistry & Biochemistry, University of Denver, Denver, CO 80210, USA; Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80210, USA.
  • 2. Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80210, USA; Department of Biological Sciences, University of Denver, Denver, CO 80210, USA.
  • 3. Department of Chemistry & Biochemistry, University of Denver, Denver, CO 80210, USA. Electronic address: [email protected].
  • 4. Department of Chemistry & Biochemistry, University of Denver, Denver, CO 80210, USA; Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80210, USA. Electronic address: [email protected].
  • 5. Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80210, USA; Department of Biological Sciences, University of Denver, Denver, CO 80210, USA. Electronic address: [email protected].
  • 6. Department of Chemistry & Biochemistry, University of Denver, Denver, CO 80210, USA; Knoebel Institute for Healthy Aging, University of Denver, Denver, CO 80210, USA. Electronic address: [email protected].
PMID: 40480222 DOI: 10.1016/j.str.2025.05.006
Abstract

Many proteins implicated in neurodegenerative diseases (e.g., trans-active response DNA binding protein 43 kDa [TDP43]) interact with nucleic acids, including RNA G-quadruplexes (G4s). We here investigate whether RNA G4s play a role in TDP43 condensation in biophysical and cellular models. We find that G4s modulate TDP43 aggregation in vitro and condensation in multiple cell types, including yeast, HEK293T, and motor-neuron-like NSC-34 cells. In yeast cells, treatment with G4s causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G4-binding small molecules causes an increase in G4 stability that also stabilizes TDP43 and reduces TDP43 condensation induced by proteasomal or oxidative stress. Finally, in NSC-34 cells overexpressing exogenous TDP43, we show that G4s co-localize with TDP43 condensates under stress conditions, and treatment with G4-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest exploring treating protein misfolding diseases by targeting specific RNA structures such as G4s.

Keywords
ALS; G-quadruplex; TDP-43; TDP43; condensation.
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