Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy.
Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy.
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用于研究亨廷顿病发病机制和治疗的转基因动物模型。
DOI：
10.2147/dddt.s58470
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Li XJ
中科院分区：
文献类型：
--
作者：
Chang R;Liu X;Li S;Li XJ
亨廷顿舞蹈病（HD）是由一种基因突变引起的，该突变导致亨廷顿蛋白n端区域的聚谷氨酰胺扩增。因此，这种多q扩增导致突变亨廷顿蛋白的错误折叠和聚集以及年龄依赖性神经变性。HD的基因突变允许产生多种动物模型，表达不同形式的突变亨廷顿蛋白并表现出不同的病理。这些动物模型的研究为HD的发病机制提供了重要的见解。HD小鼠模型包括在不同细胞类型中普遍或选择性表达n端或全长突变的huntingtin的转基因小鼠，以及在内源性水平表达全长突变Htt的敲入小鼠。大型动物，如猪、羊和猴子，也被用于生成动物高清模型。本文综述了常用的转基因HD小鼠模型和转基因HD大型动物模型的不同特点，并讨论了如何利用它们来识别潜在的治疗方法。由于HD与其他神经退行性疾病具有许多共同的病理特征，因此确定HD的治疗方法也将有助于开发有效的治疗方法，以治疗同样由蛋白质错误折叠引起的不同神经退行性疾病，并以年龄依赖性的方式发生。
Huntington’s disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner.