Dataset Information

Epigallocatechin-3-gallate restores hippocampal proteomic alterations driven by Dyrk1A overexpression in mice

ABSTRACT: The inhibition of DYRK1A (Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A) activity, triplicated in trisomy 21 subjects, has been proved as a promising therapy for Down syndrome. Epigallocatechin-3-gallate (EGCG), a polyphenol of green tea, is an allosteric inhibitor of DYRK1A that showed beneficial pro-cognitive effects in clinical trials with DS individuals. However, EGCG induces several pharmacological effects, and there is no proof that the observed improvements result from DYRK1A inhibition. Besides, the direct consequences of Dyrk1A overexpression are not well defined. We therefore used quantitative proteomics to decipher the proteome and phosphoproteome alterations resulting from Dyrk1A overexpression and its inhibition to get insight into the mechanism of action of EGCG. Towards this aim, we used mice overexpressing Dyrk1A, and compared the hippocampal proteome and phosphoproteome with their wild type counterparts, in basal conditions, and after treatment with EGCG. Moreover, given that the human clinical trials found that the effects of EGCG potentiated the effects of cognitive stimulation, we also included in our study treatment with environmental enrichment and its combination with EGCG. We found that DYRK1A overexpression leads to alterations in protein and phosphoprotein levels of hundreds of proteins, and that the levels of proteins involved in key postsynaptic pathways are restored by the cognitive enhancer treatments, which could help conceiving new therapeutic strategies.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hippocampus

DISEASE(S): Down Syndrome

SUBMITTER: Eduard Sabidó

LAB HEAD: Eduard Sabidó

PROVIDER: PXD010689 | Pride | 2019-12-11

REPOSITORIES: Pride

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			Action	DRS
	141124_S_MOES_01_03_2ug_240min.raw	Raw
	141124_S_MOES_02_01_2ug_240min.raw	Raw
	141124_S_MOES_03_01_2ug_240min.raw	Raw
	141124_S_MOES_04_01_2ug_240min.raw	Raw
	141124_S_MOES_05_01_2ug_240min.raw	Raw

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Publications

DYRK1A Overexpression Alters Cognition and Neural-Related Proteomic Pathways in the Hippocampus That Are Rescued by Green Tea Extract and/or Environmental Enrichment.

De Toma Ilario I Ortega Mireia M Aloy Patrick P Sabidó Eduard E Dierssen Mara M

Frontiers in molecular neuroscience 20191115

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for <i>Dyrk1a</i> (TgDyrk1A) and in a trisomic DS mouse model (Ts65Dn). Interestingly, paired with cognitive stimulation, green tea has beneficial pro-cognitive effects in DS individuals. Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (<i> ...[more]

PMID: 31803016

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Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Experiment Overall Design: Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Five independent (Dyrk1A overexpression, five individual samples) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dye-swapping experiments).

Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Experiment Overall Design: Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL2872, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Of 44,290 spots, 2756 are controls. The remaining 41,534 spots represent 33,661 unique transcripts which correspond to 20,202 unique human genes. Four dependent (152F7, one series of pooled samples) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dye-swapping experiments).

Project description:Transcription profiling of transgenic down syndrome mouse model to show the role of DYRK1A gene. The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1Adosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Transgenic embrionic brain regions versus wild type mice were analysed. The log2 values represent Cy5/Cy3 ratio (transgenic Cy5/wild type Cy3). Each array was scanned under a green laser (543 nm for Cy3 labeling) or a red laser (633 nm for Cy5 labeling) using a ScanArray Lite scanning confocal fuorescent scanner with 10 u resolution (laser power: 85% for Cy5 and 90% for Cy3, gain: 75% for Cy5 and 70% for Cy3). Scanned output files were analyzed using the GenePix Pro 3.0 software. Each spot was defined by automatic positioning of a grid of circles over the image. The average and median pixel intensity ratios calculated from both channels and the local background of each spot were determined. Local background corrected intensity ratios was determined for each spot. The background-corrected expression data were filtered for flagged spots and weak signal. Normalization was performed by the global Lowess method. Studentâs t-test was applied to determine the p value.