A common gene expression signature in Huntington's disease patient brain regions.
A common gene expression signature in Huntington's disease patient brain regions.
复制标题
DOI：
10.1186/s12920-014-0060-2
复制
发表时间：
2014-10-30
影响因子：
2.7
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Neueder A;Bates GP
基因表达数据为疾病机制提供了宝贵的见解。亨廷顿舞蹈病（HD）是一种由亨廷顿蛋白基因三核苷酸重复扩增引起的神经退行性疾病，据报道存在广泛的转录失调。传统的失调分析表明，例如在死后HD大脑的尾状核中，大约三分之一的基因表达水平发生了改变。由于大量的基因失调，表达变化的潜在相关性往往在难以理解的庞大基因列表中丢失。为了解决这一问题，我们对HD死后脑区基因表达数据集进行了加权相关网络分析。我们能够在HD小脑中发现先前未被识别的转录失调，其中包含与尾状核和额叶皮质BA4区域共同的基因表达特征。此外，我们发现一些不相关的通路，例如全局mRNA加工，在HD中失调。我们提供的证据表明，与先前的发现相反，突变的亨廷顿蛋白足以诱导小脑和额叶皮质BA4区域的应激反应基因子集。HD与其他神经退行性疾病的比较表明，免疫系统，特别是补体系统，通常是激活的。我们还证明，HD小鼠模型很好地模拟了疾病的某些方面，而其他方面，例如免疫系统的激活没有得到充分反映。我们的分析为HD的分子发病机制提供了新的见解，并确定了作为潜在治疗靶点的基因和途径。本文的在线版本（doi:10.1186/s12920-014-0060-2）包含补充材料，可供授权用户使用。
Gene expression data provide invaluable insights into disease mechanisms. In Huntington’s disease (HD), a neurodegenerative disease caused by a tri-nucleotide repeat expansion in the huntingtin gene, extensive transcriptional dysregulation has been reported. Conventional dysregulation analysis has shown that e.g. in the caudate nucleus of the post mortem HD brain the gene expression level of about a third of all genes was altered. Owing to this large number of dysregulated genes, the underlying relevance of expression changes is often lost in huge gene lists that are difficult to comprehend. To alleviate this problem, we employed weighted correlation network analysis to archival gene expression datasets of HD post mortem brain regions. We were able to uncover previously unidentified transcription dysregulation in the HD cerebellum that contained a gene expression signature in common with the caudate nucleus and the BA4 region of the frontal cortex. Furthermore, we found that yet unassociated pathways, e.g. global mRNA processing, were dysregulated in HD. We provide evidence to show that, contrary to previous findings, mutant huntingtin is sufficient to induce a subset of stress response genes in the cerebellum and frontal cortex BA4 region. The comparison of HD with other neurodegenerative disorders showed that the immune system, in particular the complement system, is generally activated. We also demonstrate that HD mouse models mimic some aspects of the disease very well, while others, e.g. the activation of the immune system are inadequately reflected. Our analysis provides novel insights into the molecular pathogenesis in HD and identifies genes and pathways as potential therapeutic targets. The online version of this article (doi:10.1186/s12920-014-0060-2) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
24
作者：
Barth, Andreas S.;Kuner, Ruprecht;Sueltmann, Holger
通讯作者：
Sueltmann, Holger
影响因子：
14.5
作者：
Fassunke, Jana;Majores, Michael;Becker, Albert J.
通讯作者：
Becker, Albert J.
影响因子：
11.4
作者：
Hayashida, Naoki;Fujimoto, Mitsuaki;Nakai, Akira
通讯作者：
Nakai, Akira
影响因子：
4.7
作者：
Anglada-Huguet, Marta;Giralt, Albert;Xifro, Xavier
通讯作者：
Xifro, Xavier
影响因子：
3.5
作者：
Fardaei, M;Rogers, MT;Brook, JD
通讯作者：
Brook, JD