UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Ahmed, MM; Dhanasekaran, AR; Tong, S; Wiseman, FK; Fisher, EM; Tybulewicz, VL; Gardiner, KJ; (2013) Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain. Human Molecular Genetics , 22 (9) 1709 -1724. 10.1093/hmg/ddt017. Green open access

[thumbnail of Hum._Mol._Genet.-2013-Ahmed-1709-24.pdf]
Preview
PDF
Hum._Mol._Genet.-2013-Ahmed-1709-24.pdf

Download (470kB)

Abstract

Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ∼120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.

Type: Article
Title: Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddt017
Publisher version: http://dx.doi.org/ 10.1093/hmg/ddt017
Language: English
Additional information: © The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permission@oup.com PMCID: PMC3613160
Keywords: Adaptor Proteins, Signal Transducing, Animals, Brain, Calcium-Binding Proteins, Disease Models, Animal, Down Syndrome, Female, Gene Expression Profiling, Gene Expression Regulation, Guanine Nucleotide Exchange Factors, Male, Mice, Mice, Inbred C57BL, Neoplasm Proteins, Nerve Growth Factors, Phosphorylation, Receptors, N-Methyl-D-Aspartate, S100 Calcium Binding Protein beta Subunit, S100 Proteins, TOR Serine-Threonine Kinases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/1386051
Downloads since deposit
148Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item