加拿大多伦多大学Christopher E. Pearson及其团队研究发现滑动的CAG DNA结合小分子可在体内诱导三核苷酸重复收缩。2020年2月14日出版的《自然-遗传学》杂志发表了这项成果。

他们报告了一种化合物，萘啶-氮杂喹诺酮（NA），它特异性结合扩展突变的滑移CAG DNA中间产物，而该突变此前从未被怀疑过。NA有效诱导亨廷顿舞蹈病（HD）患者细胞中的重复收缩以及HD小鼠纹状体中棘神经元的整体收缩。

收缩对于扩展的等位基因而言是特异的，与DNA复制无关，它需要在编码的CTG链上转录并通过阻止CAG滑脱的修复而产生。NA诱导的收缩取决于MutSβ驱动的主动扩增。在HD小鼠纹状体中进行NA注射可减少突变型HTT蛋白聚集，这是HD发病机理和严重程度的生物标志。重复结构特异性DNA配体是收缩扩展重复序列的新途径。

据了解，在许多诸如HD的重复序列有关疾病中，受影响组织中不断的重复扩增会导致疾病发作、进展和恶化。通过外源因子诱导扩增重复序列的收缩尚不可能。传统方法将靶向驱动重复突变的蛋白质。

附：英文原文

Title: A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo

Author: Masayuki Nakamori, Gagan B. Panigrahi, Stella Lanni, Terence Gall-Duncan, Hideki Hayakawa, Hana Tanaka, Jennifer Luo, Takahiro Otabe, Jinxing Li, Akihiro Sakata, Marie-Christine Caron, Niraj Joshi, Tanya Prasolava, Karen Chiang, Jean-Yves Masson, Marc S. Wold, Xiaoxiao Wang, Marietta Y. W. T. Lee, John Huddleston, Katherine M. Munson, Scott Davidson, Mehdi Layeghifard, Lisa-Monique Edward, Richard Gallon, Mauro Santibanez-Koref, Asako Murata, Masanori P. Takahashi, Evan E. Eichler, Adam Shlien, Kazuhiko Nakatani, Hideki Mochizuki, Christopher E. Pearson, Masayuki Nakamori, Gagan B. Panigrahi, Stella Lanni, Terence Gall-Duncan, Hideki Hayakawa, Hana Tanaka, Jennifer Luo, Takahiro Otabe, Jinxing Li, Akihiro Sakata, Marie-Christine Caron, Niraj Joshi, Tanya Prasolava, Karen Chiang, Jean-Yves Masson, Marc S. Wold, Xiaoxiao Wang, Marietta Y. W. T. Lee, John Huddleston, Katherine M. Munson, Scott Davidson, Mehdi Layeghifard, Lisa-Monique Edward, Richard Gallon, Mauro Santibanez-Koref, Asako Murata, Masanori P. Takahashi, Evan E. Eichler, Adam Shlien, Kazuhiko Nakatani, Hideki Mochizuki, Christopher E. Pearson

Issue&Volume: 2020-02-14

Abstract: 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 MutSβ. 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.

DOI: 10.1038/s41588-019-0575-8

Source: https://www.nature.com/articles/s41588-019-0575-8