Wang Yuqin, Mulligan Claire, Denyer Gareth, Delom Frederic, Dagna-Bricarelli Franca, Tybulewicz Victor L J, Fisher Elizabeth M C, Griffiths William J, Nizetic Dean, Groet Jürgen
Institute of Mass-Spectrometry, School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, United Kingdom.
Mol Cell Proteomics. 2009 Apr;8(4):585-95. doi: 10.1074/mcp.M800256-MCP200. Epub 2008 Nov 10.
Down syndrome, caused by the trisomy of chromosome 21, is a complex condition characterized by a number of phenotypic features, including reduced neuron number and synaptic plasticity, early Alzheimer disease-like neurodegeneration, craniofacial dysmorphia, heart development defects, increased incidence of childhood leukemia, and powerful suppression of the incidence of most solid tumors. Mouse models replicate a number of these phenotypes. The Tc1 Down syndrome model was constructed by introducing a single supernumerary human chromosome 21 into a mouse embryonic stem cell, and it reproduces a large number of Down syndrome phenotypes including heart development defects. However, little is still known about the developmental onset of the trisomy 21-induced mechanisms behind these phenotypes or the proteins that are responsible for them. This study determined the proteomic differences that are present in undifferentiated embryonic stem cells and are caused by an additional human chromosome 21. A total of 1661 proteins were identified using two-dimensional liquid chromatography followed by tandem mass spectrometry from whole embryonic stem cell lysates. Using isobaric tags for relative and absolute quantification, we found 52 proteins that differed in expression by greater than two standard deviations from the mean when an extra human chromosome 21 was present. Of these, at least 11 have a possible functional association with a Down syndrome phenotype or a human chromosome 21-encoded gene. This study also showed that quantitative protein expression differences in embryonic stem cells can persist to adult mouse as well as reproduce in human Down syndrome fetal tissue. This indicates that changes that are determined in embryonic stem cells of Down syndrome could potentially identify proteins that are involved in phenotypes of Down syndrome, and it shows that these cell lines can be used for the purpose of studying these pathomechanisms.
唐氏综合征由21号染色体三体性引起，是一种复杂病症，具有多种表型特征，包括神经元数量减少和突触可塑性降低、早期类似阿尔茨海默病的神经退行性变、颅面畸形、心脏发育缺陷、儿童白血病发病率增加以及大多数实体瘤发病率受到强力抑制。小鼠模型复制了其中一些表型。Tc1唐氏综合征模型是通过将一条额外的人类21号染色体引入小鼠胚胎干细胞构建而成的，它再现了包括心脏发育缺陷在内的大量唐氏综合征表型。然而，对于21号染色体三体性诱导这些表型背后的机制的发育起始，或者负责这些机制的蛋白质，我们仍然知之甚少。本研究确定了未分化胚胎干细胞中由额外的人类21号染色体导致的蛋白质组差异。使用二维液相色谱随后进行串联质谱分析，从整个胚胎干细胞裂解物中总共鉴定出1661种蛋白质。使用等压标签进行相对和绝对定量，我们发现当存在额外的人类21号染色体时，有52种蛋白质的表达差异大于均值的两个标准差。其中，至少有11种蛋白质可能与唐氏综合征表型或人类21号染色体编码基因存在功能关联。本研究还表明，胚胎干细胞中的定量蛋白质表达差异在成年小鼠中也会持续存在，并且在人类唐氏综合征胎儿组织中也会重现。这表明在唐氏综合征胚胎干细胞中确定的变化可能潜在地识别出参与唐氏综合征表型的蛋白质，并且表明这些细胞系可用于研究这些病理机制。
