A novel and accurate full-length HTT mouse model for Huntington's disease.
A novel and accurate full-length HTT mouse model for Huntington's disease.
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作者：
Shenoy SA;Zheng S;Liu W;Dai Y;Liu Y;Hou Z;Mori S;Tang Y;Cheng J;Duan W;Li C
本研究利用细菌人工染色体（BAC）系统构建了一种新型的亨廷顿病（HD）小鼠模型BAC 226 Q，表达了含有约226个CAG-CAA重复序列的全长人HTT，并含有内源性人HTT启动子和调控元件。BAC 226 Q概括了年龄依赖性和进行性HD样表型的全谱，没有不需要的和错误的表型。BAC 226 Q小鼠发育正常，并在2个月时逐渐表现出HD样精神和认知表型。从3到4个月，BAC 226 Q小鼠显示出强烈的进行性运动缺陷。在11个月时，BAC 226 Q小鼠显示出显著缩短的寿命、逐渐的体重减轻，并表现出神经病理学，包括纹状体和皮质特异性的显著脑萎缩、纹状体神经元死亡、广泛的亨廷顿蛋白包涵体和反应性病理学。因此，新的BAC 226 Q小鼠准确地再现了稳健的、年龄依赖性的、进行性的HD样表型，将是研究疾病机制、鉴定生物标志物和测试HD的基因靶向治疗方法的有价值的工具。
Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.