Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain.
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.
Department of Pediatrics, Linda Crnic Institute for Down Syndrome, University of Colorado Denver School of Medicine, 12700 E 19th Avenue, Aurora, CO 80045, USA.
Md Mahiuddin
MM
Ahmed
A Ranjitha
AR
Dhanasekaran
Suhong
S
Tong
Frances K
FK
Wiseman
Elizabeth M C
EM
Fisher
Victor L J
VL
Tybulewicz
Katheleen J
KJ
Gardiner
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D016194:Receptors, N-Methyl-D-Aspartate; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C534905:Tcim protein, mouse; C513260:Tiam1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases