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. 2013 May 1;22(9):1709-24.
doi: 10.1093/hmg/ddt017. Epub 2013 Jan 24.

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

Md Mahiuddin Ahmed  1 , A Ranjitha Dhanasekaran, Suhong Tong, Frances K Wiseman, Elizabeth M C Fisher, Victor L J Tybulewicz, Katheleen J Gardiner
Affiliations

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

Md Mahiuddin Ahmed et al. Hum Mol Genet. .

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.

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Figures

Figure 1.
Figure 1.
TIAM1 and S100B are overexpressed in Tc1 mice. Expression levels of HSA21 proteins TIAM1 and S100B, and the S100B receptor, RAGE, were examined by westerns blots. Representative gels are shown for (A) cortex, (C) hippocampus. For TIAM1, gels were 8% acrylamide to separate the four bands that range from 70 to ∼200 kDa; for S100B (12 kDa) and RAGE (46 kDa), gels were 12% acrylamide. Representative actin signals, used for normalization, are also shown. C, euploid control; T, trisomic Tc1. (B and D) Results of quantitation from two to three replicate gels as in (A) and (C). For comparison, euploid control values were set to 100%. The unpaired Student t-test was used to calculate the mean genotype differences; bars indicate standard error of the mean; *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 2.
Figure 2.
Individual variation in levels of RCAN1 and APP. Scatter plots show that RCAN1 levels in Tc1 mice are more variable than in euploid controls. APP levels are shown for comparison. Nether RCAN1 nor APP are expressed from the Tc1 HSA21 chromosome and neither shows an average increase in Tc1 mice.
Figure 3.
Figure 3.
Variation in protein expression levels. Levels of six proteins determined by RPA are shown in individual euploid controls (white bars) and Tc1 (black bars), in the cortex, hippocampus and cerebellum. Average levels of all six proteins in Tc1 relative to controls are given in Table 1. (A and C) DYRK1A and SOD1 are trisomic in Tc1 mice; (B) ITSN1 is deleted in the Tc1 chromosome and therefore functionally disomic; (D, E and F) Levels of non-HSA21 signaling proteins, pERK1/2, pELK and GSK3B.
Figure 4.
Figure 4.
Variation in IEG protein levels. Levels of non-HSA21 proteins (A) CFOS, (B) pCFOS and (C) ARC, determined by RPA, are shown in individual euploid controls (white bars) and Tc1 (black bars) in cortex and hippocampus. Relative to euploid controls, average levels of all three proteins are elevated in the hippocampus but not the cortex of Tc1.
Figure 5.
Figure 5.
Correlations among HSA21 proteins ITSN1 and DYRK1A and components of the MAP kinase signaling cascade. (A) cortex; (B and C) hippocampus. Correlations with r> 0.8, with linear scatter plots and P < 0.05 (Spearman correlation analysis) were considered significant and are shown. Heavy solid lines, correlations seen in controls and Tc1; thin solid lines, correlations seen only in controls; dashed lines, correlations seen only in Tc1. All correlations are positive. Grey circles, HSA21 proteins; open circles, non-HSA21 proteins. Phosphorylation-dependent and -independent forms are shown separately. Asterisk indicates average levels are increased in Tc1 with respect to controls.
Figure 6.
Figure 6.
Correlations involving the HSA21 protein TIAM1 in hippocampus. (A) With subunits of the NMDA receptor and the HSA21 protein APP, (B) with GSK3B and HSA21 proteins RCAN1 and DYRK1A. Correlations between protein levels were determined by Spearman correlation analysis; only correlations with r > 0.8, with linear scatter plots and P < 0.05 are shown. Heavy solid lines, correlations seen in controls and Tc1; thin solid lines, correlations seen only in controls; dashed lines, correlations seen only in Tc1. Grey circles, HSA21 proteins; open circles, non-HSA21 proteins. Phosphorylation-dependent and -independent forms are shown separately; pGSK3B_T, pTyr216; pGSK3B_S, pSer9. N, negative correlation. Asterisk indicates average protein levels are increased in Tc1 with respect to controls.
Figure 7.
Figure 7.
Correlation involving Immediate Early Gene (IEG) proteins in (A) hippocampus and (B) cortex. Correlations between protein levels were determined by Spearman correlation analysis; only correlations with r > 0.8, with linear scatter plots and P < 0.05 are shown. Heavy solid lines, correlations seen in controls and Tc1; thin solid lines, correlations seen only in controls; dashed lines, correlations seen only in Tc1. Dark grey circles, IEG proteins; light grey circles, HSA21 proteins; open circles, non-IEG, non-HSA21 proteins. Phosphorylation-dependent and -independent forms are shown separately. N, negative correlation. Asterisk indicates average protein levels are increased in Tc1 with respect to controls.
Figure 8.
Figure 8.
Chromosome 21 long-arm and orthologous mouse chromosome 16 region trisomic in the Tc1 and the Ts65Dn mice, respectively. D1, segment of HSA21 present in Tc1 and absent in Ts65Dn; grey-shaded D2, D3, internal deletions in the Tc1 HSA21 chromosome. R1, region of mouse chromosome 17 uniquely trisomic in the Ts65Dn; R2, HSA21 orthologous region of mouse chromosome 16 trisomic in the Ts65Dn; R3, HSA21 segment uniquely trisomic in the Tc1. RefSeqP, number of HSA21 annotated classical protein coding genes trisomic in the Tc1, and the number of mouse orthologs trisomic in the Ts65Dn (9). The complete list of protein-coding genes trisomic in regions D1–D3 and R1–R3 and additional details of Tc1 gene-specific partial deletions and duplications are provided in Supplementary Material, Table S6.
Figure 9.
Figure 9.
Comparison of protein expression abnormalities in Tc1 and Ts65Dn. All proteins with an average expression level significantly different from corresponding controls in at least one brain region of at least one mouse model are listed at right. Proteins are grouped by general category. Yellow, increased; blue, decreased; black, unchanged; grey, not measured. % difference from respective controls are provided in Table 1 for Tc1 and in Supplementary Material, Table S4 for Ts65Dn (13). Cr, cortex; HP, hippocampus; CB, cerebellum.
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