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

Nature Medicinevolume 24pages802813 (2018) | Download Citation

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Abstract

Alpha-thalassemia X-linked intellectual disability (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 to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 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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Acknowledgements

We thank I. Kitajima for kindly providing AtrxΔE2 mice, deposited in the RIKEN BioResource Center (RBRC04937), H. Shimbo for kindly assisting in cell culture, D. Picketts for kindly providing the Atrx cDNA (pEGFP-C2-ATRX-HA) plasmid, N. Berube for kindly providing the ATRX shRNA (pSUPER-shATRX1) plasmid and K. Kosik for kindly providing the GFP-MS2-nls and MS2-binding site–CaMKII-α 3′ UTR plasmids. This research was supported by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED; N.S., K.K., H.T., N.O., H.S., K.F. and T.W.). This work was also supported by MEXT/JSPS KAKENHI (grant numbers 16K08265 and 25110705) to N.S.

Author information

Affiliations

  1. Department of Biofunctional Analysis Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu, Japan

    • Norifumi Shioda
  2. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    • Yasushi Yabuki
    • , Kouya Yamaguchi
    • , Misaki Onozato
    •  & Kohji Fukunaga
  3. Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan

    • Yue Li
    •  & Hiroshi Sugiyama
  4. Division of Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

    • Kenji Kurosawa
  5. Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Japan

    • Hideyuki Tanabe
  6. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan

    • Nobuhiko Okamoto
  7. Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan

    • Takumi Era
  8. Department of Medical Ethics and Medical Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    • Takahito Wada

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Contributions

N.S., Y.Y., K.Y., M.O. and Y.L. performed the experiments. K.K., H.T., N.O., T.E., H.S. and T.W. provided critical advice. N.S. and K.F. wrote the manuscript and designed the study. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Norifumi Shioda or Takahito Wada or Kohji Fukunaga.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–13 and Supplementary Tables 1–5

  2. Reporting Summary

  3. Supplementary Video 1

    Time-lapse imaging of GFP-MS2-labeled CaMKIIα mRNA (GFP-CaMKIIα 3′ UTR) in a proximal dendrite of a cultured WT neuron

  4. Supplementary Video 2

    Time-lapse imaging of GFP-MS2-labeled CaMKIIα mRNA (GFP-CaMKIIα 3′ UTR) in a distal dendrite of a cultured WT neuron

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https://doi.org/10.1038/s41591-018-0018-6