| RRC ID |
69796
|
| 著者 |
Shibata T, Nagano K, Ueyama M, Ninomiya K, Hirose T, Nagai Y, Ishikawa K, Kawai G, Nakatani K.
|
| タイトル |
Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
12(1)
|
| ページ |
236
|
| 公開日 |
2021-1-11
|
| DOI |
10.1038/s41467-020-20487-4
|
| PII |
10.1038/s41467-020-20487-4
|
| PMID |
33431896
|
| PMC |
PMC7801683
|
| MeSH |
Animals
Base Sequence
Cell Nucleus / metabolism
Disease Models, Animal
Drosophila / genetics*
HeLa Cells
Humans
Introns / genetics
Magnetic Resonance Spectroscopy
Models, Molecular
Nucleic Acid Conformation
Phenotype
Phosphorylation
RNA / genetics*
RNA-Binding Proteins / metabolism
Small Molecule Libraries / pharmacology
Temperature
|
| IF |
12.121
|
| リソース情報 |
| ヒト・動物細胞 |
HeLa(RCB0007) |
