Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD) is a form of dementia characterized by amyloid-β plaques and Tau neurofibrillary tangles that progressively disrupt neural circuits in the brain. Using mass spectrometry, we performed a combined analysis of the tyrosine, serine, and threonine phosphoproteome, and proteome of post-mortem brain tissue from AD patients and aged matched controls. We used a data-centric approach to identify co-correlated signaling networks associated with cellular and pathological changes. We identified two independent pathology clusters that were associated with Tau and oligodendrocyte pathologies. We observed phosphorylation sites on known Tau-kinases as well as other novel signaling factors that were associated with these clusters. Together, these results build a map of pathology-associated phosphorylation signaling activation events occurring in AD.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Nader Morshed

LAB HEAD: Forest Michael White

PROVIDER: PXD020087 | Pride | 2021-05-25

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Project description:This study sought to explore phosphoproteome signaling dysregulation in different models of neurodegeneration. We collected phosphotyrosine, MAPK/CDK substrates, global phosphoproteome, and protein expression data from hippocampus and/or cortex tissue from each model. Tryptic peptides were multiplexd with TMT, enriched for phosphopeptides, and then identified and quantified by LC-MS/MS. We additionally quantified phosphotyrosine peptides from BV-2 cells expressing various Siglec receptor constructs.

2020-11-09 | PXD018757 | Pride

Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition

Project description:A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a human BRAF-mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent signals, and three distinct and reversible phase transitions toward quiescence. Statistical inference of kinetically-defined regulatory modules revealed a concerted response to oncogenic BRAF inhibition and a dominant compensatory induction of SRC family kinase (SFK) signaling, which we found to be at least partially driven by accumulation of reactive oxygen species via impaired redox homeostasis. This induction sensitized cells to co-treatment with an SFK inhibitor across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the translational potential for measuring the temporal dynamics of signaling and transcriptional networks under therapeutic challenge.

2024-02-27 | PXD048479 | Pride

Truncated Tau - Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms

Project description:Tau is a microtubule-associated protein that ensures neuronal shape and function. Besides, Tau is a central player in Alzheimer’s disease (AD) and related Tauopathies where it is found aggregated in degenerating neurons. Mechanisms leading to Tau pathology and its progression are far from being elucidated. Among Tau species found in AD brains, several yet unidentified truncated Tau fragments are showed. A major step forward in the understanding of the role of Tau truncation would be to identify the precise cleavage sites of Tau species. This key step is mandatory to generate appropriate experimental tools in order to investigate the impact of each identified truncated-species on Tau function/dysfunction. Here, we achieved an optimized proteomics approach and succeed in identifying a number of new N-terminally truncated-Tau species from human brain. As N-terminal residues of these fragments are located broadly across Tau sequence, one could expect to have different effects on Tau. We initiated cell-based functional studies by analyzing biochemical characteristics of two N-terminally truncated Tau species starting at residues Met11 and Gln124 (accordingly to the longest Tau isoform) regarding Tau microtubule function. Our results surprisingly showed that the ability of Tau to bind and stabilize microtubules was greater when the first 123 residues are truncated, suggesting that Tau N-terminus would have a role in regulation of microtubule stabilization. Overall, future studies based on our new N-terminally truncated-Tau species will provide new knowledge on the role of truncation in Tau biology as well as in AD pathological process.

2015-05-15 | PXD001353 | Pride

RNA-seq and TRAP-seq of astrocytes and brain tissue in mouse models of Alzheimer's pathology

Project description:Alzheimer’s disease is known to alter astrocytes, but the effect of Aß and Tau pathology on these cells remains poorly understood. We investigated the transcriptomic behaviour of astrocytes (via translating ribosome affinity purification (TRAP)), and bulk brain tissue, in mouse models of APP/PS1 ß-amyloidopathy and MAPT-P301S tauopathy, in a mouse model overexpressing cytoprotective Nrf2 specifically in astrocytes (GFAP-Nrf2 model), and in crosses between the amyloidopathy and tauopathy models with the GFAP-Nrf2 mouse.

2021-12-02 | E-MTAB-10985 | biostudies-arrayexpress

Deep Dive in the Proteome of Human Cerebrospinal Fluid: A Valuable Data Resource for Biomarker Discovery and Missing Protein Identification

Project description:Cerebrospinal fluid (CSF) is a body fluid of choice for biomarker studies of brain disorders but remains relatively under-studied compared to other biological fluids such as plasma, partly due to the more invasive means of its sample collection. The present study establishes an in-depth CSF proteome through the analysis of a unique CSF sample from a pool of healthy donors. After immuno-affinity depletion, the CSF sample was fractionated using off-gel electrophoresis and analyzed with liquid chromatography tandem mass spectrometry (MS) using the latest generation of hybrid Orbitrap mass spectrometers. The shotgun proteomic analysis allowed the identification of 20689 peptides mapping on 3379 proteins. To the best of our knowledge, the obtained dataset constitutes the largest CSF proteome published so far. Among the CSF proteins identified, 34% correspond to genes defined as elevated in the brain by The Human Protein Atlas. The principal Alzheimer disease biomarkers (e.g., tau protein, amyloid-β, apolipoprotein E and neurogranin) were detected. Importantly, our dataset significantly contributes to the Chromosome-Centric Human Proteome Project (C-HPP), and 13 proteins considered as missing are proposed for validation in accordance with the HPP guidelines.

2018-08-29 | PXD009646 | Pride

TIA1 interactome from mouse cortex

Project description:The purpose of this experiment was to characterize the network of proteins that interact with TIA1, and to investigate whether tau exerts control over TIA1 protein interactions, TIA1 was immunoprecipitated from cortical brain tissue of 10 month-old WT (C57BL/6J), tau-/- and TIA1-/- mice. The specificity of the TIA1 IP was verified by immunoblotting with anti-TIA1 antibody (Fig. 3A), and the resulting TIA1 proteome was examined by mass spectrometry.

2018-10-26 | PXD003922 | Pride

Role of Fnr1 and Fnr3 in transcriptional regulation under oxygen limitation in Herbaspirillum seropedicae

Project description:To determine the direct promoter targets of Fnr proteins, we correlated transcriptional changes observed in single fnr1 and fnr3 mutants (E-MTAB-5741) with ChIP-Seq analysis, taking advantage of C-terminally 3xFlag fnr alleles engineered into the H. seropedicae genome. ChIP-seq data were obtained from cultures grown under limited oxygen availability. Using this approach, DNA-binding targets for the H. seropedicae Fnr1 and Fnr3 proteins were unambiguously revealed and correlated with transcript profiles to determine the specific regulons of each protein.

2018-02-26 | E-MTAB-6395 | biostudies-arrayexpress

Alzheimer's Disease Dataset

Project description:FK506 binding protein 51kDa (FKBP51/FKBP5) is part of a mature heat shock protein 90kDa (Hsp90) chaperone complex that preserves tau. Microarray analysis of human brains reveal that FKBP51 gene expression selectively increased with age and Alzheimer's disease, which correlated with demethylation of the regulatory regions in the FKBP5 gene. Moreover, FKBP51 levels significantly correlated with Braak pathological staging. In addition, we show that in brains devoid of FKBP51, tau levels are reduced. Recombinant FKBP51 and Hsp90 synergize to block tau clearance through the proteasome and produce T22-positive tau oligomers. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved tau species, including phosphorylated and oligomeric tau that have been linked to Alzheimer's disease pathogenesis. FKBP51 blocked amyloid formation and decreased tangle load in the brain. These alterations in tau turnover and aggregate structure culminated in enhanced neurotoxicity. We propose a model where age-associated increases in FKBP51 levels can out-compete the association of other pro-degradation Hsp90 co-chaperones, resulting in neurotoxic tau accumulation. Thus, strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 could be therapeutically relevant for Alzheimer's disease and other tauopathies. These AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 Postmortem brain tissue was collected from ADRC brain banks. Cases were preferentially selected where 3 or more brain regions were available

2014-04-21 | E-GEOD-48350 | biostudies-arrayexpress

Simple, single-shot phosphoproteomic analysis of heat-stable tau

Project description:We developed a simple, antibody-free approach for single shot analysis of tau phosphorylation across the entire protein by liquid-chromatography tandem mass spectrometry (LC-MS/MS) to study age-related changes in tau phosphorylation. This methodology is species independent; thus, while initially developed in a rodent model, we utilized this technique to analyze 36 phosphorylation sites on rhesus monkey tau from the prefrontal cortex (PFC), a region vulnerable to AD degeneration. We identified novel, age-related changes in tau phosphorylation in the rhesus monkey PFC and analyzed patterns of phosphorylation change across domains of the protein. We confirmed a significant increase and positive correlation with age of phosphorylated serine235 tau and phosphorylated serine396 tau levels in an expanded cohort of 14 monkeys.

2021-11-25 | PXD027971 | Pride

Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling

Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

2024-01-26 | PXD044740 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data