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

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  • Shioda Norifumi
    Department of Biofunctional Analysis Laboratory of Molecular Biology, Gifu Pharmaceutical University, Japan
  • Sugiyama Hiroshi
    Department of Chemistry, Graduate School of Science, Kyoto University, Japan
  • Wada Takahito
    Department of Medical Ethics and Medical Genetics, Graduate School of Medicine, Kyoto University, Japan
  • Fukunaga Kohji
    Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

説明

<p>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.</p>

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