Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats
Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats
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DOI：
10.1002/cne.10776
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发表时间：
2003-10-06
影响因子：
2.5
通讯作者：
Chesselet, MF
中科院分区：
文献类型：
--
作者：
Menalled, LB;Sison, JD;Chesselet, MF
亨廷顿病（HD）是由编码亨廷顿蛋白的基因中CAG重复序列的异常扩增引起的。HD治疗的开发需要在动物模型中进行药物的临床前试验，这些动物模型重现了HD中观察到的功能障碍和区域特异性病理学。我们已经开发了一种新的基因敲入小鼠模型的HD嵌合小鼠/人外显子1含有140 CAG重复插入在小鼠亨廷顿基因。这些小鼠在1月龄时表现出运动活动和直立增加，随后在4月龄时活动减退，1岁时步态异常。行为症状出现在神经病理异常之前，仅在4个月大时才变得强烈和广泛。这些包括亨廷顿蛋白的核染色和含亨廷顿蛋白的核和神经元聚集体，这些聚集体首先出现在纹状体、丘脑核和嗅结节中。有趣的是，具有早期病理学的区域都接收密集的多巴胺能输入，支持多巴胺在HD病理学中的作用的累积证据。核染色和聚集体主要分布在纹状体和大脑皮层的II/III层和深层V，而神经元聚集体则分布在苍白球和大脑皮层的IV层/浅层V。嗅觉系统显示早期和显着的聚集体积累，这可能是相关的早期赤字在HD患者的气味辨别观察。由于它们的早期行为异常和区域特异性病理，这些小鼠提供了一个强大的工具，以评估新疗法的有效性和研究涉及HD的神经病理学机制。J.（C）2003 Wiley-Liss，Inc.
Huntington's disease (HD) is caused by an abnormal expansion of CAG repeats in the gene encoding huntingtin. The development of therapies for HD requires preclinical testing of drugs in animal models that reproduce the dysfunction and regionally specific pathology observed in HD. We have developed a new knock-in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene. These mice displayed an increased locomotor activity and rearing at 1 month of age, followed by hypoactivity at 4 months and gait anomalies at 1 year. Behavioral symptoms preceded neuropathological anomalies, which became intense and widespread only at 4 months of age. These consisted of nuclear staining for huntingtin and huntingtin-containing nuclear and neuropil aggregates that first appeared in the striatum, nucleus accumbens, and olfactory tubercle. Interestingly, regions with early pathology all receive dense dopaminergic inputs, supporting accumulating evidence for a role of dopamine in HD pathology. Nuclear staining and aggregates predominated in striatum and layer II/III and deep layer V of the cerebral cortex, whereas neuropil aggregates were found in the globus pallidus and layer IV/ superficial layer V of the cerebral cortex. The olfactory system displayed early and marked aggregate accumulation, which may be relevant to the early deficit in odor discrimination observed in patients with HD. Because of their early behavioral anomalies and regionally specific pathology, these mice provide a powerful tool with which to evaluate the effectiveness of new therapies and to study the mechanisms involved in the neuropathology of HD. J. (C) 2003 Wiley-Liss, Inc.