In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.
In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.
复制标题
在纹状体而非皮层神经元中表达突变亨廷顿蛋白的小鼠中，揭示了体内细胞自主转录异常。
DOI：
10.1093/hmg/ddq548
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发表时间：
2011
影响因子：
3.5
通讯作者：
Ehrlich,MichelleE
中科院分区：
文献类型：
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作者：
Thomas,ElizabethA;Coppola,Giovanni;Tang,Bin;Kuhn,Alexandre;Kim,SoongHo;Geschwind,DanielH;Brown,TimothyB;Luthi-Carter,Ruth;Ehrlich,MichelleE
亨廷顿病 (HD) 是由亨廷顿蛋白 (HTT) 基因中的 CAG 重复扩增引起的，其特征是蛋白质聚集异常以及运动和认知功能障碍。 Htt 蛋白普遍表达，但纹状体中棘神经元 (MSN) 最容易出现功能障碍和死亡。基因表达异常是 HD 的核心致病特征，但细胞自主和非细胞自主效应对转录的相对作用仍不清楚。为了确定纹状体体内细胞自主失调的程度，我们检查了有症状的 D9-N171-98Q（又名 DE5）转基因小鼠的全基因组 RNA 表达，其中具有 98Q 重复扩展的人类 Htt 的前 171 个氨基酸的前脑表达仅限于 MSN。将这些小鼠生成的微阵列数据与在相同阵列平台上从泛神经元 HD 小鼠模型 R6/2（携带两种不同的 CAG 重复长度）生成的微阵列数据进行比较，发现基因表达变化存在相对高度的重叠。我们进一步关注与兴奋性毒性、氧化应激、线粒体功能障碍、多巴胺信号传导和营养支持相关的已知经典途径。虽然与兴奋性毒性、多巴胺信号传导和营养支持相关的基因在 DE5 和 R6/2 小鼠中发生了改变，这可能是细胞自主的或非细胞自主的，但与线粒体功能障碍、氧化应激和过氧化物酶体增殖物激活受体相关的基因主要在 DE5 转基因小鼠中受到影响，表明细胞自主机制。总体而言，HD 诱导的纹状体转录组失调在很大程度上归因于突变体 Htt 的内在影响，而皮质神经元中没有表达。
Huntington's disease (HD), caused by a CAG repeat expansion in thehuntingtin(HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatumin vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.