Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome

[Speaker] Norifumi Shioda:1
[Co-author] Hiroshi Sugiyama:2, Takahito Wada:3, Kohji Fukunaga:4
1:Department of Biofunctional Analysis Laboratory of Molecular Biology, Gifu Pharmaceutical University, Japan, 2:Department of Chemistry, Graduate School of Science, Kyoto University, Japan, 3:Department of Medical Ethics and Medical Genetics, Graduate School of Medicine, Kyoto University, Japan, 4:Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

ATR-X syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind G-rich sequences with high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant Xlr3b expression in mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX affects G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression together with DNMTs by DNA methylation. Xlr3b binds dendritic mRNAs, and its overexpression inhibits dendritic transport of CaMKIIalpha mRNA, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is metabolized to porphyrins, protoporphyrin IX and hemin, reduces RNA polymerase II recruitment and represses Xlr3b transcription by modifying G-quadruplex structure. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.
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