Small molecule targeting r(UGGAA) n disrupts RNA foci and alleviates disease phenotype in Drosophila model
Autor: | Kensuke Ninomiya, Kazuhiko Nakatani, Yoshitaka Nagai, Morio Ueyama, Tomonori Shibata, Kinya Ishikawa, Tetsuro Hirose, Konami Nagano, Gota Kawai |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Multidisciplinary Chemistry Science General Physics and Astronomy RNA General Chemistry 010402 general chemistry medicine.disease 01 natural sciences Phenotype Small molecule General Biochemistry Genetics and Molecular Biology 0104 chemical sciences Cell biology 03 medical and health sciences 030104 developmental biology RNA splicing Spinocerebellar ataxia medicine Nucleic acid structure Trinucleotide repeat expansion Function (biology) |
Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) |
ISSN: | 2041-1723 |
Popis: | 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. Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here the authors show the mechanism by which a small molecule targets the disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31. |
Databáze: | OpenAIRE |
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