Manipulating TDP43 Aggregation via RNA G-quadruplexes

Abstract

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.