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首页> 外文期刊>BMC Medical Genomics >Validation of microarray data in human lymphoblasts shows a role of the ubiquitin-proteasome system and NF- k B in the pathogenesis of Down syndrome
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Validation of microarray data in human lymphoblasts shows a role of the ubiquitin-proteasome system and NF- k B in the pathogenesis of Down syndrome

机译：验证人类淋巴母细胞中的微阵列数据显示了遍在蛋白-蛋白酶体系统和NF-κB在唐氏综合症发病机理中的作用

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Background Down syndrome (DS) is a complex disorder caused by the trisomy of either the entire, or a critical region of chromosome 21 (21q22.1-22.3). Despite representing the most common cause of mental retardation, the molecular bases of the syndrome are still largely unknown. Methods To better understand the pathogenesis of DS, we analyzed the genome-wide transcription profiles of lymphoblastoid cell lines (LCLs) from six DS and six euploid individuals and investigated differential gene expression and pathway deregulation associated with trisomy 21. Connectivity map and PASS-assisted exploration were used to identify compounds whose molecular signatures counteracted those of DS lymphoblasts and to predict their therapeutic potential. An experimental validation in DS LCLs and fetal fibroblasts was performed for the most deregulated GO categories, i.e. the ubiquitin mediated proteolysis and the NF- k B cascade. Results We show, for the first time, that the level of protein ubiquitination is reduced in human DS cell lines and that proteasome activity is increased in both basal conditions and oxidative microenvironment. We also provide the first evidence that NF- k B transcription levels, a paradigm of gene expression control by ubiquitin-mediated degradation, is impaired in DS due to reduced I k B-alfa ubiquitination, increased NF- k B inhibitor (I k B-alfa) and reduced p65 nuclear fraction. Finally, the DSCR1/DYRK1A/NFAT genes were analysed. In human DS LCLs, we confirmed the presence of increased protein levels of DSCR1 and DYRK1A, and showed that the levels of the transcription factor NFATc2 were decreased in DS along with a reduction of its nuclear translocation upon induction of calcium fluxes. Conclusions The present work offers new perspectives to better understand the pathogenesis of DS and suggests a rationale for innovative approaches to treat some pathological conditions associated to DS.
机译：背景唐氏综合症（DS）是由21号染色体（21q22.1-22.3）的整个区域或关键区域的三体性引起的复杂疾病。尽管代表了智力低下的最常见原因，但该综合征的分子基础仍然未知。方法为了更好地了解DS的发病机制，我们分析了来自6个DS和6个整倍体个体的淋巴母细胞样细胞系（LCL）的全基因组转录谱，并研究了与21三体性相关的差异基因表达和通路失调。勘探被用来鉴定其分子特征与DS淋巴母细胞的分子特征相反的化合物，并预测其治疗潜力。在DS LCL和胎儿成纤维细胞中，对最失控的GO类别（即泛素介导的蛋白水解和NF-κB级联）进行了实验验证。结果我们首次显示，在人DS细胞系中蛋白质泛素化水平降低，并且在基础条件和氧化微环境下蛋白酶体活性均增加。我们还提供了第一个证据，即由于IkB-α泛素化减少，NF-κB抑制剂增加（I k B），DS损害了由泛素介导的降解控制基因表达的范式NF-k B转录水平。 -α）和降低的p65核分数。最后，分析了DSCR1 / DYRK1A / NFAT基因。在人DS LCL中，我们证实了DSCR1和DYRK1A蛋白质水平的增加，并表明转录因子NFATc2的水平在DS中降低，并且在诱导钙通量时其核易位减少。结论本工作为更好地理解DS的发病机理提供了新的观点，并为治疗与DS相关的某些病理状况的创新方法提供了理论依据。

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