Reynolds Caicedo, K. M. | bioRxiv Science

bioRxiv2025

G-quadruplex sequence dictates tau oligomerization and fibril morphology

Previous studies have identified that non-canonical nucleic acid structures known as G-quadruplexes (G4s) modulate protein aggregation and could play major roles in neurodegenerative diseases. Here we examine the presence and protein oligomerization activity of G4s that are enriched in human hippocampal aggregates. We found these G4s to be powerful, sequence-specific modulators of aggregation. Different G4s facilitated aggregate propagation in cells, caused tau to form distinct protein oligomer populations, and seeded tau fibrils with different fibril structure and length. This study highlights the importance of nucleic acid composition within aggregates, where small changes in nucleotide sequence and topology can vastly alter protein interactions, oligomerization, and fibrillization.

biochemistry↗

bioRxiv2024

Manipulating TDP43 Aggregation via RNA G-quadruplexes

The events that lead to protein misfolding diseases are not fully understood. Many proteins implicated in neurodegenerative diseases (e.g., TDP43) interact with nucleic acids, including RNA G-quadruplexes. In this work, we investigate whether RNA G-quadruplexes play a role in TDP43 condensation in biophysical and cellular models. We find that G-quadruplexes 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 G-quadruplexes causes increased TDP43 accumulation in cells before cellular death. In HEK293T cells expressing TDP43, incubation with G-quadruplex-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 G-quadruplexes co-localize with TDP43 condensates under stress conditions and treatment with G-quadruplex-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest that a novel future approach to explore for treating protein misfolding diseases may be to target specific RNA structures such as G-quadruplexes.

molecular biology↗