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Nat Commun. 2017 Oct 31;8(1):1212. doi: 10.1038/s41467-017-01422-6.

Systematic proteome and proteostasis profiling in human Trisomy 21 fibroblast cells.

Author information

1
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093, Zurich, Switzerland.
2
Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, 1211, Geneva, Switzerland.
3
Cellular Networks and Systems Biology, University of Cologne, CECAD, University of Cologne, 50931, Cologne, Germany.
4
Department of Experimental Oncology, European Institute of Oncology, 20139, Milan, Italy.
5
Institute of Biochemistry, Department of Biology, ETH Zurich, 8093, Zurich, Switzerland.
6
Department of Oncology and Hemato-Oncology, University of Milan, 20122, Milan, Italy.
7
Cellular Networks and Systems Biology, University of Cologne, CECAD, University of Cologne, 50931, Cologne, Germany. andreas.beyer@uni-koeln.de.
8
Department of Genetic Medicine and Development, University of Geneva Medical School, and University Hospitals of Geneva, 1211, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.
9
iGE3 Institute of Genetics and Genomics of Geneva, 1211, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.
10
Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093, Zurich, Switzerland. aebersold@imsb.biol.ethz.ch.
11
Faculty of Science, University of Zurich, 8057, Zurich, Switzerland. aebersold@imsb.biol.ethz.ch.

Abstract

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.

PMID:
29089484
PMCID:
PMC5663699
DOI:
10.1038/s41467-017-01422-6
[Indexed for MEDLINE]
Free PMC Article

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