Menalled Liliana B, Sison Jessica D, Dragatsis Ioannis, Zeitlin Scott, Chesselet Marie-Françoise
Department of Neurology, University of California at Los Angeles, Los Angeles, California 90095, USA.
J Comp Neurol. 2003 Oct 6;465(1):11-26. doi: 10.1002/cne.10776.
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.
亨廷顿舞蹈症（HD）由编码亨廷顿蛋白的基因中CAG重复序列异常扩增所致。HD治疗方法的开发需要在动物模型中对药物进行临床前测试，这些动物模型要能再现HD中观察到的功能障碍和区域特异性病理变化。我们构建了一种新的HD基因敲入小鼠模型，其嵌合的小鼠/人类外显子1含有140个CAG重复序列，插入到小鼠亨廷顿基因中。这些小鼠在1月龄时表现出运动活性增加和竖毛行为，随后在4月龄时活动减少，1岁时出现步态异常。行为症状先于神经病理异常出现，神经病理异常仅在4月龄时才变得强烈且广泛。这些异常包括亨廷顿蛋白的核染色以及含亨廷顿蛋白的核内和神经纤维聚集体，它们首先出现在纹状体、伏隔核和嗅结节。有趣的是，早期出现病理变化的区域均接受密集的多巴胺能输入，这支持了多巴胺在HD病理中起作用的证据不断积累。核染色和聚集体在纹状体以及大脑皮层的II/III层和深层V层中占主导，而神经纤维聚集体则出现在苍白球和大脑皮层的IV层/浅层V层。嗅觉系统显示出早期且明显的聚集体积累，这可能与HD患者早期的气味辨别缺陷有关。由于这些小鼠具有早期行为异常和区域特异性病理变化，它们为评估新疗法的有效性以及研究HD神经病理学所涉及的机制提供了一个强大的工具。
