Department of Pediatrics, Federico II University, Naples 80131, Italy.
BMC Med Genomics. 2013 Jul 5;6:24. doi: 10.1186/1755-8794-6-24.
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.
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-kB cascade.
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-kB transcription levels, a paradigm of gene expression control by ubiquitin-mediated degradation, is impaired in DS due to reduced IkB-alfa ubiquitination, increased NF-kB inhibitor (IkB-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.
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.
唐氏综合征（DS）是一种由 21 号染色体（21q22.1-22.3）的全部或关键区域三体引起的复杂疾病。尽管它是智力障碍的最常见原因，但该综合征的分子基础仍在很大程度上未知。
为了更好地了解 DS 的发病机制，我们分析了来自 6 名 DS 患者和 6 名正常二倍体个体的淋巴母细胞系（LCL）的全基因组转录谱，并研究了与 21 三体相关的差异基因表达和途径失调。连接图谱和 PASS 辅助探索用于识别分子特征与 DS 淋巴母细胞相反的化合物，并预测其治疗潜力。对最失调的 GO 类别（泛素介导的蛋白水解和 NF-kB 级联）进行了 DS LCL 和胎儿成纤维细胞的实验验证。
我们首次表明，人 DS 细胞系中的蛋白泛素化水平降低，并且在基础条件和氧化微环境下蛋白酶体活性增加。我们还首次提供了证据表明，由于 IkB-alfa 泛素化减少、NF-kB 抑制剂（IkB-alfa）增加和 p65 核部分减少，NF-kB 转录水平（泛素介导的降解控制基因表达的范例）在 DS 中受损。最后，分析了 DSCR1/DYRK1A/NFAT 基因。在人 DS LCL 中，我们证实了 DSCR1 和 DYRK1A 的蛋白水平增加，并表明转录因子 NFATc2 的水平在 DS 中降低，并且在诱导钙流时其核易位减少。
本研究为更好地了解 DS 的发病机制提供了新的视角，并为治疗与 DS 相关的某些病理状况提供了创新方法的依据。
