Transgenic mice in the study of polyglutamine repeat expansion diseases
Transgenic mice in the study of polyglutamine repeat expansion diseases
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DOI：
10.1111/j.1750-3639.1998.tb00196.x
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发表时间：
1998-10-01
期刊：
影响因子：
6.4
通讯作者：
Davies, SW
中科院分区：
文献类型：
--
作者：
Bates, GP;Mangiarini, L;Davies, SW
越来越多的神经退行性疾病，包括亨廷顿病 (HD)，被发现是由 CAG/聚谷氨酰胺扩增引起的。我们通过将携带高度扩增的 CAG 重复序列的人类 HD 基因的外显子 1 引入小鼠种系中，生成了 HD 小鼠模型。这些小鼠发展出进行性神经表型。在有症状的小鼠大脑中发现了对亨廷顿蛋白和泛素具有免疫反应性的神经元核内包涵体 (NII)，体外分析表明，内含物是通过聚谷氨酰胺重复序列自聚集形成淀粉样蛋白样原纤维，该纤维由交叉 P-片结构（称为极性拉链）组成。对患者材料和其他转基因品系的分析现已表明 NII 是所有这些疾病的共同特征。在转基因模型中，内含物出现在症状出现之前，表明存在因果关系。相反，神经变性发生在表型出现之后，表明症状是由神经元功能障碍而不是原代细胞死亡引起的。
An increasing number of neurodegenerative diseases, including Huntington's disease (HD), have been found to be caused by a CAG/polyglutamine expansion, We have generated a mouse model of HD by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line, These mice develop a progressive neurological phenotype, Neuronal intranuclear inclusions (NII) that are immunoreactive for huntingtin and ubiquitin have been found in the brains of symptomatic mice, In vitro analysis indicates that the inclusions are formed through self aggregation via the polyglutamine repeat into amyloid-like fibrils composed of a cross P-sheet structure that has been termed a polar zipper. Analysis of patient material and other transgenic lines has now shown NII to be a common feature of all of these diseases. In the transgenic models, inclusions are present prior to the onset of symptoms suggesting a causal relationship, In contrast, neurodegeneration occurs after the onset of the phenotype indicating that the symptoms are caused by a neuronal dysfunction rather than a primary cell death.