A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo
A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo
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DOI：
10.1073/pnas.0408936102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Kazantsev, AG
中科院分区：
文献类型：
--
作者：
Zhang, XQ;Smith, DL;Kazantsev, AG
多聚谷氨酰胺（polyQ）疾病，包括亨廷顿病（HD），是由在其他不相关的基因产物内的polyQ编码重复序列的扩增引起的。在polyQ疾病中，受影响神经元的病理和死亡与不溶性聚集体中突变蛋白的积累相关。几项研究暗示polyQ依赖性聚集是HD神经变性的原因，表明抑制神经元polyQ聚集可能对HD患者有治疗作用。我们已经使用基于酵母的高通量筛选测定来鉴定polyQ聚集的小分子抑制剂。我们验证了四种命中化合物在基于哺乳动物细胞的HD模型中的作用，优化了化合物结构的效力，然后在体外培养的HD转基因小鼠脑切片中对其进行了测试。这些努力确定了一种有效的化合物（IC50 = 10 nM），对HD神经元中的polyQ聚集具有长期抑制作用。在果蝇HD模型中测试该化合物显示其抑制体内神经变性，强烈表明polyQ聚集在HD病理学中的重要作用。在该筛选中鉴定的聚集抑制剂代表了四种主要的化学支架，并且是用于开发人类polyQ疾病治疗剂的强先导化合物。
Polyglutamine (polyQ) disorders, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. In polyQ diseases, the pathology and death of affected neurons are associated with the accumulation of mutant proteins in insoluble aggregates. Several studies implicate polyQ-dependent aggregation as a cause of neurodegeneration in HD, suggesting that inhibition of neuronal polyQ aggregation may be therapeutic in HD patients. We have used a yeast-based high-throughput screening assay to identify small-molecule inhibitors of polyQ aggregation. We validated the effects of four hit compounds in mammalian cell-based models of HD, optimized compound structures for potency, and then tested them in vitro in cultured brain slices from HD transgenic mice. These efforts identified a potent compound (IC50 = 10 nM) with long-term inhibitory effects on polyQ aggregation in HD neurons. Testing of this compound in a Drosophila HD model showed that it suppresses neurodegeneration in vivo, strongly suggesting an essential role for polyQ aggregation in HD pathology. The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases.