ArticleBMC medical genomics2013
Validation of microarray data in human lymphoblasts shows a role of the ubiquitin-proteasome system and NF-kB in the pathogenesis of Down syndrome.
Article in BMC medical genomics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
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- Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome.Antioxidants (Basel, Switzerland) · 2022Article
- TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment.Cellular and molecular neurobiology · 2022Review
- The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives.Frontiers in cellular neuroscience · 2022Review
- Down syndrome is an oxidative phosphorylation disorder.Redox biology · 2021Article
- Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19.Scientific reports · 2021Article
- Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome.Trends in molecular medicine · 2020Article
- LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice.Molecular neurobiology · 2019Article
- Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21.Omics : a journal of integrative biology · 2017Article
- Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D.Scientific reports · 2017Article
- A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells.BMC cancer · 2016Article
- Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.Neuron · 2015Article
- Stem and progenitor cell dysfunction in human trisomies.EMBO reports · 2015Review
- DNA microarray-based gene expression profiling of estrogenic chemicals.Cellular and molecular life sciences : CMLS · 2014Review
- Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches.Journal of neural transmission (Vienna, Austria : 1996) · 2014Article
- Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
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.
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