The CAG repeat expansion that elongates the polyglutamine tract in huntingtin is the root genetic cause of Huntington’s Disease (HD), a debilitating neurodegenerative disorder. This seemingly slight change to the primary amino acid sequence alters the physical structure of the mutant protein and alters its activity. We have identified a set of G-quadruplex-forming DNA aptamers (MS1, MS2, MS3, MS4) that bind mutant huntingtin proximal to lysines K2932/K2934 in the carboxyl-terminal CTD-II domain. Aptamer-binding to mutant huntingtin, abrogated the enhanced polycomb repressive complex 2 (PRC2) stimulatory-activity conferred by the expanded polyglutamine tract. In HD, but not normal, neuronal progenitor cells (NPC), MS3 aptamer co-localized with endogenous mutant huntingtin and was associated with significantly decreased PRC2 activity. Furthermore, MS3 transfection protected HD NPC against starvation-dependent stress with increased ATP. Therefore, DNA aptamers can preferentially target mutant huntingtin and modulate a gain of function endowed by the elongated polyglutamine segment. These mutant huntingtin binding aptamers provide novel molecular tools for delineating the effects of the HD mutation and encourage mutant huntingtin structure-based approaches to therapeutic development.

使亨廷顿蛋白中的聚谷氨酰胺束伸长的CAG重复扩增是亨廷顿氏病（HD）（一种使人衰弱的神经退行性疾病）的根本遗传原因。一级氨基酸序列的这种看似微小的变化改变了突变蛋白的物理结构，并改变了其活性。我们已经确定了一组形成G-四链体的DNA适体（MS1，MS2，MS3，MS4），它们在羧基末端CTD-II域中与赖氨酸K2932 / K2934附近的突变亨廷顿蛋白结合。与突变体亨廷顿蛋白的适体结合，废除了由扩展的聚谷氨酰胺束赋予的增强的多梳抑制复合物2（PRC2）的刺激活性。在高清，但不是正常的神经元祖细胞（NPC）中，MS3适体与内源性突变亨廷顿蛋白共定位，并且与PRC2活性显着降低有关。此外，MS3转染可保护HD NPC免受ATP升高导致的饥饿依赖性应激。因此，DNA适体可以优先靶向突变的亨廷顿蛋白，并调节延长的聚谷氨酰胺片段赋予的功能。这些突变的亨廷顿蛋白结合适体提供了新颖的分子工具来描述HD突变的作用，并鼓励基于突变的亨廷顿蛋白结构的方法进行治疗开发。