2. Academic Validation
  3. The effect of G-quadruplexes on TDP43 condensation, distribution, and toxicity

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

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: erich.chapman@gmail.com.
  • 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: sunil.kumar97@du.edu.
  • 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: daniel.linseman@du.edu.
  • 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: scott.horowitz@du.edu.
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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