Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons

Jose Moruno-Manchon (1) , Pauline Lejault (2) , Yaoxuan Wang (1) , Brenna Mccauley (3) , Pedram Honarpisheh , Diego Morales Scheihing , Shivani Singh , Weiwei Dang , Nayun Kim , Akihiko Urayama , Liang Zhu , David Monchaud (2) , Louise Mccullough , Andrey Tsvetkov

1 UT Dallas - University of Texas at Dallas [Richardson]
2 ICMUB - Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon]
3 BCM - Baylor College of Medicine

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.

Domaines: Neurobiologie

Jose Moruno-Manchon, Pauline Lejault, Yaoxuan Wang, Brenna Mccauley, Pedram Honarpisheh, et al.. Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons. eLife, 2020, 9, ⟨10.7554/eLife.52283⟩. ⟨hal-02475218⟩