Development of a mutant allele-specific transcriptional repressive agent in CAG/CTG triplet repeat diseases
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- Matsuo Kazuya
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ.
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- Ikenoshita Susumu
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ.
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- Yabuki Yasushi
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ.
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- Kawakubo Kosuke
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ.
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- Asamitsu Sefan
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ. Lab. Neuroepitranscriptom., RIKEN BDR
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- Sugiyama Hiroshi
- Dept. Chem., Grad. Sch. Sci., Kyoto Univ.
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- Shioda Norifumi
- Dept. Gene Neurol., Inst. Mol. Embryol. Genet. (IMEG), Kumamoto Univ.
Bibliographic Information
- Other Title
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- CAG/CTGトリプレットリピート疾患における変異アレル特異的転写抑制剤の開発
Abstract
<p>Expansion of CAG and CTG (CWG) triplet repeats is causal in a number of inherited neurological diseases. The CWG triplet repeat diseases can be broadly classified into coding and non-coding types based on their location in the genome, such as Huntington's disease (HD) by expanded CAG repeat in a coding region and myotonic dystrophy type-1 (DM1) by expanded CTG repeat in a 3'-untranslated region. The CWG repeat diseases are thought to induce complex pathogenic mechanisms through expanded CWG repeat-derived RNAs and polypeptides. Here we show a CWG repeat DNA targeting compound, cyclic Pyrrole-Imidazole Polyamide (CWG-cPIP) suppresses the pathogenesis of coding and non-coding CWG repeat diseases. CWG-cPIP binds to hairpin form of the mismatched CWG DNA, interfering with transcriptional elongation of RNA polymerase in a repeat length-dependent manner. CWG-cPIP inhibits pathogenic mRNA transcripts from expanded CWG repeat, result in reduction of CUG RNA foci and polyglutamine accumulations in DM1 and HD patient cells and mouse models, respectively. Treatment with CWG-cPIP also ameliorates learning and memory deficits and synaptic dysfunction in DM1 and HD mouse models with less off-target effects. Taken together, we present a novel candidate compound that targets expanded CWG repeat DNA independent of genomic location, demonstrating the concept of reducing the levels of pathogenic RNAs and proteins.</p>
Journal
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- Proceedings for Annual Meeting of The Japanese Pharmacological Society
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Proceedings for Annual Meeting of The Japanese Pharmacological Society 96 (0), YIA08-1-, 2022
Japanese Pharmacological Society
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Keywords
Details 詳細情報について
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- CRID
- 1390576037462740352
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- ISSN
- 24354953
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- Text Lang
- ja
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- Data Source
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- JaLC
- Crossref
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- Abstract License Flag
- Disallowed