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

• Main Authors: Jose F Moruno-Manchon, Pauline Lejault, Yaoxuan Wang, Brenna McCauley, Pedram Honarpisheh, Diego A Morales Scheihing, Shivani Singh, Weiwei Dang, Nayun Kim, Akihiko Urayama, Liang Zhu, David Monchaud, Louise D McCullough, Andrey S Tsvetkov
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-02-01
• Series: eLife
• Subjects: autophagy; G-quadruplex; aging; neurodegeneration; neurons
• Online Access: https://elifesciences.org/articles/52283

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.