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

eLife

Andrey S Tsvetkov¹  David Monchaud²  Diego A Morales Scheihing²  Louise D McCullough³  Weiwei Dang⁴  Akihiko Urayama⁴  Jose F Moruno-Manchon⁵  Yaoxuan Wang⁵  Pedram Honarpisheh⁶  Liang Zhu⁶  Shivani Singh⁶  Nayun Kim⁷  Brenna McCauley⁷  Pauline Lejault⁸ 

[1] Department of Internal Medicine, The University of Texas McGovern Medical School at Houston, Houston, United States;The University of Texas Graduate School of Biomedical Sciences, Houston, United States;Biostatistics and Epidemiology Research Design Core Center for Clinical and Translational Sciences, The University of Texas McGovern Medical School at Houston, Houston, United States;Department of Microbiology and Molecular Genetics, The University of Texas McGovern Medical School at Houston, Houston, United States;Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, United States;Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, United States;Huffington Center on Aging, Baylor College of Medicine, Houston, United States;Institut de Chimie Moléculaire (ICMUB), UBFC Dijon, CNRS UMR6302, Dijon, France;

关键词: autophagy;    G-quadruplex;    aging;    neurodegeneration;    neurons;   

DOI  :  10.7554/eLife.52283

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown