A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
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DOI：
10.1038/s41588-019-0575-8
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发表时间：
2020-02-14
期刊：
影响因子：
30.8
通讯作者：
Pearson, Christopher E.
中科院分区：
文献类型：
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作者：
Nakamori, Masayuki;Panigrahi, Gagan B.;Pearson, Christopher E.
在许多重复疾病中，例如亨廷顿病 (HD)，受影响组织中持续的重复扩张会导致疾病的发作、进展和严重程度。通过外源性试剂诱导扩增重复序列的收缩尚不可能。传统方法会针对驱动重复突变的蛋白质。在这里，我们报道了一种化合物，萘啶-氮杂喹诺酮 (NA)，它特异性结合扩展突变的滑动 CAG DNA 中间体，这是一个以前未被怀疑的目标。 NA 有效诱导 HD 患者细胞的重复收缩以及 HD 小鼠纹状体中型多棘神经元的集体收缩。收缩是扩展等位基因特有的，与 DNA 复制无关，需要跨编码 CTG 链的转录，并通过阻止 CAG 滑出的修复而产生。 NA 引起的收缩依赖于 MutS beta 驱动的主动扩张。 HD 小鼠纹状体中的 NA 注射可减少突变 HTT 蛋白聚集体，这是 HD 发病机制和严重程度的生物标志物。重复结构特异性 DNA 配体是收缩扩展重复序列的新途径。萘啶-氮杂喹诺酮特异性结合滑动的 CAG DNA 中间体，诱导扩展重复序列的收缩，并减少亨廷顿病细胞和动物模型中突变 HTT 蛋白的聚集。
In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutS beta. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.Naphthyridine-azaquinolone specifically binds slipped-CAG DNA intermediates, induces contractions of expanded repeats and reduces mutant HTT protein aggregates in cell and animal models of Huntington's disease.