Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons
Jose F. Moruno-Manchon, Pauline Lejault, Yaoxuan Wang, Brenna S. McCauley, Pedram Honarpisheh, Diego Morales‐Scheihing, Shivani Singh, Weiwei Dang, Nayun Kim, Akihiko Urayama, Liang Zhu, David Monchaud, Louise D. McCullough, Andrey S. Tsvetkov
Abstract
Guanine-rich DNA sequences can fold into four-stranded G-quadruplex (G4-DNA) structures. G4-DNA regulates replication and transcription, at least in cancer cells. Here, we demonstrate that, in neurons, pharmacologically stabilizing G4-DNA with G4 ligands strongly downregulates the Atg7 gene. Atg7 is a critical gene for the initiation of autophagy that exhibits decreased transcription with aging. Using an in vitro assay, we show that a putative G-quadruplex-forming sequence (PQFS) in the first intron of the Atg7 gene folds into a G4. An antibody specific to G4-DNA and the G4-DNA-binding protein PC4 bind to the Atg7 PQFS. Mice treated with a G4 stabilizer develop memory deficits. Brain samples from aged mice contain G4-DNA structures that are absent in brain samples from young mice. Overexpressing the G4-DNA helicase Pif1 in neurons exposed to the G4 stabilizer improves phenotypes associated with G4-DNA stabilization. Our findings indicate that G4-DNA is a novel pathway for regulating autophagy in neurons.