Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease
Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease
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DOI：
10.1073/pnas.1603871113
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发表时间：
2016-05-17
影响因子：
11.1
通讯作者：
Mehler, Mark F.
中科院分区：
文献类型：
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作者：
Molero, Aldrin E.;Arteaga-Bracho, Eduardo E.;Mehler, Mark F.
最近的研究发现亨廷顿病（HD）敲入小鼠模型和相关胚胎干细胞系中的神经诱导以及纹状体和皮质神经发生受损。然而，这些发育改变对 HD 发病机制和进展的潜在作用目前尚不清楚。为了解决这个问题，我们使用了 BACHD:CAG-Cre(ERT2) 小鼠，该小鼠携带突变型亨廷顿蛋白 (mHtt)，经过修饰后含有含有致病性多谷氨酰胺扩展 (Q97) 的 floxed 外显子 1。出生后第 21 天施用他莫昔芬后，floxed mHtt-exon1 被去除，mHtt 表达终止 (Q97(CRE))。这些条件小鼠在一生中表现出与表达 mHtt 的小鼠相似的损伤特征：(i) 纹状体神经变性，(ii) 早期易受 NMDA 介导的兴奋性毒性影响，(iii) 运动协调损伤，(iv) 纹状体电生理活动的暂时明显异常，以及 (v) 皮质纹状体功能连接性和可塑性改变。这些发现强烈表明发育畸变可能在 HD 发病机制和进展中发挥重要作用。
Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-Cre(ERT2) mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97(CRE)). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.