Mechanism of allele-selective inhibition of huntingtin expression by duplex RNAs that target CAG repeats: function through the RNAi pathway.
Mechanism of allele-selective inhibition of huntingtin expression by duplex RNAs that target CAG repeats: function through the RNAi pathway.
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DOI：
10.1093/nar/gks907
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发表时间：
2012-12
影响因子：
14.9
通讯作者：
Corey DR
中科院分区：
文献类型：
--
作者：
Hu J;Liu J;Yu D;Chu Y;Corey DR
亨廷顿氏病是一种无法治愈的神经退行性疾病，由亨廷顿蛋白（HTT）基因的一个等位基因内CAG三核苷酸重复扩增引起。阻断突变型HTT表达并保持野生型HTT表达的药物针对疾病的病因，是一种替代治疗方法。我们之前已经证明，与扩展的三核苷酸重复序列互补的含有错配的双工rna是突变HTT表达的有效和等位基因选择性抑制剂，但等位基因选择性的机制尚未探索。我们现在报道，抗cag双工RNA优先将argonaute 2 （AGO2）招募到突变型而不是野生型HTT mRNA。有效抑制突变体HTT蛋白表达所需的AGO2比抑制野生型表达所需的AGO2要少。相反，抑制突变体HTT蛋白的表达对GW182 （TNRC6A）及其两个类似蛋白家族（与miRNA作用相关的蛋白家族）的表达降低高度敏感。等位基因选择性抑制可能涉及多个蛋白质- rna复合物与扩展重复序列的合作结合。这些数据表明，等位基因选择性抑制是通过类似于miRNAs使用的RNA干扰途径进行的，HTT mRNA突变型和野生型等位基因的区分对细胞内AGO2和GW182家族蛋白库高度敏感。
Huntington’s disease is an incurable neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat within one allele of the huntingtin (HTT) gene. Agents that block expression of mutant HTT and preserve expression of wild-type HTT target the cause of the disease and are an alternative for therapy. We have previously demonstrated that mismatch-containing duplex RNAs complementary to the expanded trinucleotide repeat are potent and allele-selective inhibitors of mutant HTT expression, but the mechanism of allele selectivity was not explored. We now report that anti-CAG duplex RNA preferentially recruits argonaute 2 (AGO2) to mutant rather than wild-type HTT mRNA. Efficient inhibition of mutant HTT protein expression requires less AGO2 than needed for inhibiting wild-type expression. In contrast, inhibiting the expression of mutant HTT protein is highly sensitive to reduced expression of GW182 (TNRC6A) and its two paralogs, a protein family associated with miRNA action. Allele-selective inhibition may involve cooperative binding of multiple protein–RNA complexes to the expanded repeat. These data suggest that allele-selective inhibition proceeds through an RNA interference pathway similar to that used by miRNAs and that discrimination between mutant and wild-type alleles of HTT mRNA is highly sensitive to the pool of AGO2 and GW182 family proteins inside cells.
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DOI：
10.1093/brain/awr333
发表时间：
2012-04
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Grondin R;Kaytor MD;Ai Y;Nelson PT;Thakker DR;Heisel J;Weatherspoon MR;Blum JL;Burright EN;Zhang Z;Kaemmerer WF
通讯作者：
Kaemmerer WF
影响因子：
16.2
作者：
Kordasiewicz HB;Stanek LM;Wancewicz EV;Mazur C;McAlonis MM;Pytel KA;Artates JW;Weiss A;Cheng SH;Shihabuddin LS;Hung G;Bennett CF;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
3.7
作者：
Hu, Jiaxin;Gagnon, Keith T.;Corey, David R.
通讯作者：
Corey, David R.
影响因子：
64.5
作者：
Eulalio, Ana;Huntzinger, Eric;Izaurralde, Elisa
通讯作者：
Izaurralde, Elisa
影响因子：
14.9
作者：
Fiszer A;Mykowska A;Krzyzosiak WJ
通讯作者：
Krzyzosiak WJ