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Abstract
BackgroundDown 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.MethodsTo 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.ResultsWe 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.ConclusionsThe 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.
Highlights
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)
In human lymphoblastoid cell lines (LCLs) and fetal fibroblasts, we provide the first evidence that the level of protein ubiquitination is reduced in DS and that proteasome activity is increased in both basal conditions and oxidative microenvironment
Supervised analysis of pooled data of DS and control samples For the analysis of differentially expressed genes, six DS LCLs were compared to six control samples
Summary
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). Down syndrome (DS) (MIM 190685) is a human complex disorder caused by the trisomy of either the entire, or a critical region of chromosome (chr) 21 (21q22.1-22.3). Gene expression studies failed to provide definitive results; evidence in human DS cells point to the presence of abnormalities of extracellular matrix, of mitochondrial function and other metabolic pathways, including purine metabolism, in fetal specimens [5,11,13], and changes in transcriptional regulation, oxidative stress and immunerelated genes in adult tissues [6,12,14,24,25]. Seventy distinct transcription factors, including RelA, NFATc1, NFATc2 and NFATc3, were identified as being affected by dosage imbalance
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