Manipulating TDP43 Aggregation via RNA G-quadruplexes

ABSTRACT The events that lead to protein misfolding diseases are poorly 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 aggregation in biophysical and cellular models. We find that G-quadruplexes modulate TDP43 aggregation in a biophysical model and 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 induces a reduction in chemically-induced TDP43 aggregation. Finally, in NSC-34 cells overexpressing TDP43, we show that G-quadruplexes co-localize with TDP43 aggregates under stress conditions and treatment with G-quadruplex-binding small molecules decreases TDP43-mediated toxicity. Together, these findings suggest that a novel approach to treating protein misfolding diseases may be to target specific RNA structures such as G-quadruplexes.