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

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.

The Water-Soluble Triptolide Derivative PG490-88 Protects against Cisplatin-Induced Acute Kidney Injury

“…Slides were stored at 4°C until use. Antibody screening was carried out as previously described (Ahmed et al, 2013). In brief, slides were incubated in blocking solution (3% bovine serum albumin; Sigma-Aldrich Co., St. Louis, MO) in Trisbuffered saline/0.1% Tween 20 (TBST) for 4 hours, followed by overnight incubation at 4°C with primary antibody.…”

“…Antibody signal for each spot was normalized to the corresponding signals from staining a different slide with the general protein stain SyproRuby, following the manufacturer's instructions (Invitrogen). Details of quantitation and review of data quality and reproducibility were as previously described (Ahmed et al, 2013).…”

Down syndrome and Alzheimer's disease: Common pathways, common goals

“…Second, the Ts65Dn is also trisomic for a small centromeric segment of mouse chromosome 17 that is not orthologous to HSA21. It has recently been shown that this segment is more gene rich than previously assumed, and indeed includes 50 protein coding genes [56], among them paralogs of some HSA21 genes, including SYNJ2 (see previously for paralog SYNJ1) and TIAM2, plus several Dynein light chain genes whose increased dosage could influence endosomal transport. Thus, the genetic basis for the phenotype of the Ts65Dn is more complex and may not be identical to DS.…”

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

“…Gardiner and collaborators have shown that Tc1 mice show many of the phenotypes characteristic of DS, including abnormalities in learning and memory and synaptic plasticity [36]. In comparison to Ts65Dn mice, the Tc1 exhibit elevated S100B calcium-binding protein, AMPK, and the mTORC1 proteins RAPTOR and downstream kinase P70S6 [62], which are important regulators of cellular metabolism and aging. Therefore, these mice may represent a novel and yet fairly unexplored model for DS, aging and AD.…”