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Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model

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  • Tomonori Shibata

    (The Institute of Scientific and Industrial Research (ISIR), Osaka University)

  • Konami Nagano

    (Chiba Institute of Technology)

  • Morio Ueyama

    (Osaka University Graduate School of Medicine)

  • Kensuke Ninomiya

    (Osaka University)

  • Tetsuro Hirose

    (Osaka University
    Institute for Genetic Medicine, Hokkaido University)

  • Yoshitaka Nagai

    (Osaka University Graduate School of Medicine)

  • Kinya Ishikawa

    (Tokyo Medical and Dental University)

  • Gota Kawai

    (Chiba Institute of Technology)

  • Kazuhiko Nakatani

    (The Institute of Scientific and Industrial Research (ISIR), Osaka University)

Abstract

Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here we report our discovery that naphthyridine carbamate dimer (NCD) targets disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31 (SCA31). Structural analysis of the NCD-UGGAA/UGGAA complex by nuclear magnetic resonance (NMR) spectroscopy clarifies the mode of binding that recognizes four guanines in the UGGAA/UGGAA pentad by hydrogen bonding with four naphthyridine moieties of two NCD molecules. Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA–protein interactions resulting in the suppression of nSB-mediated splicing events. Feeding NCD to larvae of the Drosophila model of SCA31 alleviates the disease phenotype induced by toxic r(UGGAA)n repeat RNA. These studies demonstrate that small molecules targeting toxic repeat RNAs are a promising chemical tool for studies on repeat expansion diseases.

Suggested Citation

  • Tomonori Shibata & Konami Nagano & Morio Ueyama & Kensuke Ninomiya & Tetsuro Hirose & Yoshitaka Nagai & Kinya Ishikawa & Gota Kawai & Kazuhiko Nakatani, 2021. "Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20487-4
    DOI: 10.1038/s41467-020-20487-4
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    Cited by:

    1. Yudai Yamaoki & Takashi Nagata & Keiko Kondo & Tomoki Sakamoto & Shohei Takami & Masato Katahira, 2022. "Shedding light on the base-pair opening dynamics of nucleic acids in living human cells," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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