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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Whole genome gene expression analysis of a genomic mouse model of tauopathy

ABSTRACT: The goal of this study was to assess the number and types of differentially expressed genes in a transgenic (genomic) mouse model of tau pathology. Notably, we crossed previously described genomic mouse line called â8câ that expresses all isoforms of human tau protein (Duff et al., Neurobiology of Disease, 2000;7(2):87) with a mouse tau knockout line (Dawson et al., J Cell Sci 2001;114:1179) and generated humanized mice line called âhTau Dk/Dkâ. These mice are complete knockout of endogenous mouse tau and express all six isoforms of human tau driven by the endogenous human tau promoter. We performed microarray analysis in the hippocampal tissue from six-month old hTau Dk/Dk mice (n=3) and compared it with age-matched non-transgenic control group. Both the lines are in C57BL/6J genetic background.

INSTRUMENT(S): MouseWG-6_V2_0_R3_11278593_A

ORGANISM(S): Mus musculus

SUBMITTER: Kiran Bhaskar

PROVIDER: E-MTAB-5078 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Project description:Tau (MAPT) is a microtubule-associated protein causing frequent neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA protection and P53 regulation suggests its involvement in cancer. Indeed, Tau expression correlates with cancer-specific survival or response to microtubule therapeutics. These data may imply common molecular pathways involved in the pathogenesis of neurodegenerative disorders and cancer. To bring new evidence that Tau represents a key protein in cancer, we present an in silico pan-cancer analysis of MAPT transcriptomic profile in over 11000 clinical samples and over 1300 pre-clinical samples provided by the TCGA and the DEPMAP datasets respectively. We completed this analysis by exploring a possible interplay of MAPT with wild-type or mutated P53. Then, we calculated the impact of MAPT expression on clinical outcome and drug response. Overall, the results support a relevant role of the MAPT gene in several cancer types, although the contribution of Tau to cancer appears to very much depend on the cellular context.

2022-11-27 | E-MTAB-8166 | biostudies-arrayexpress

Transcriptional Regulationand Chromatin Dynamics in Human Epithelial Cell Differentiation (ChIP-seq)

Project description:Genome-wide mapping of H3K4me1, H3K4me3 and H3K27ac in KP and DK ChIP-seq for H3K4me1, H3K4me3 and H3K27ac in KP and DK p63 profiling of DK through ChIP-seq

2016-04-04 | E-GEOD-64298 | biostudies-arrayexpress

Identification of proteins that interact with extracellularly applied fibrillar Tau assemblies

Project description:The microtubule associated protein Tau (MAPT) expressed in neurons is involved in microtubules stabilization, cell morphogenesis and axonal transport. In pathological conditions, Tau assembles into high molecular weight assemblies leading to neuropathological Tau deposits, the hallmark of several neurodegenerative diseases collectively named “tauopathies”, including Alzheimer’s disease. These pathologic Tau assemblies are released by affected neuronal cells and taken up by naïve neighbor cells, propagate from one cell to another and amplify by seeding the aggregation of endogenous Tau. In order to identify plasma membrane proteins exposed extracellularly that interact with extracellularly applied fibrillar Tau assemblies, we exposed pure-neuronal cultures to fibrillar Tau for 10 min, pulled down the associated proteins, and identified them using a proteomic-based approach. Of the six Tau isoforms produced by alternative splicing of the MAPT gene and differing from each other by the presence or absence of one or two inserts in the N-terminal part (0N, 1N or 2N) of the protein and by the presence of either three or four repeated microtubule binding motifs in the protein C-terminal part (3R or 4R), we have expressed and purified 1N3R and 1N4R Tau isoforms and further assembled them into 1N3R and 1N4R Tau fibrils. Using pull-down of whole cell lysates and mass spectrometry, we have identified proteins interacting with extracellularly applied Tau fibrils. We have performed two different experiments with either 1N3R Tau fibrils or 1N4R Tau fibrils (condition 1 and condition 2 respectively). Each condition consists in six experimental replicates of cells exposed 10 min to Tau fibrils and of the non-treated cells used as controls.

2019-01-09 | PXD009294 | Pride

Transcription profiling of hippocampus of CV mice (C57Bl x VM/Dk) inoculated with ME7 scrapie to determine the molecular events that accompany the scrapie-associated hippocampal neuropathology

Project description:A study of differential gene expression in the hippocampus of CV mice (C57Bl x VM/Dk) inoculated with ME7 scrapie to determine the molecular events that accompany the scrapie-associated hippocampal neuropathology. Analysis was performed at 170 days post infection, a timepoint that coincides with severe hippocampal neuronal loss.

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2023-02-03 | PXD033965 | Pride

Mouse gestational protein restriction: Newborn offspring liver and hindleg muscle

Project description:Gestational protein restriction is a model for low birth size. We hypothesized that taurine supplementation would protect against changes in newborn liver and muscle caused by a maternal low protein diet. Pregnant mouse dams were subjected to different diet schemes from day 1 of pregnancy until birth. Pups were killed following birth and liver and hindleg skeletal muscle taken out and frozen at -80C until analysis. Diet schemes: Normal Protein (20% casein; NP), Normal Protein + taurine (1% taurine supplementation in water ad libitum; NP+tau), Low Protein (8% casein; LP) and LP+tau The liver and muscle samples were normalized separately.

2009-11-07 | E-GEOD-12730 | biostudies-arrayexpress

Combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau

Project description:Abnormal changes in the neuronal microtubule-associated protein Tau, such as high phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer disease. Abnormal phosphorylation is thought to take place before aggregation, and therefore it is often assumed that phosphorylation predisposes Tau towards aggregation. However, the nature and extent of phosphorylation has remained ill-defined. Tau protein contains up to 85 potential phosphorylation sites (80 Ser/Thr, and 5 Tyr P-sites), many of which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, limitations in methods (e.g. in mass spectrometry of phosphorylated peptides, or antibodies against phospho-epitopes) have led to conflicting results regarding the overall degree of phosphorylation of Tau in cells. Here we present results from a new approach, that is based on native mass spectrometry analysis of intact Tau expressed in a eukaryotic cell system (Sf9) which reveals Tau in different phosphorylation states. The extent of phosphorylation is remarkably heterogeneous with up to ~20 phosphates (Pi) per molecule and distributed over 51 sites (including all P-sites published so far and additional 18 P-sites). The medium phosphorylated fraction Pm showed overall occupancies centered at 8 Pi (± 5 Pi) with a bell-shaped distribution, the highly phosphorylated fraction Ph had 14 Pi (± 6 Pi). The distribution of sites was remarkably asymmetric (with 71% of all P-sites located in the C-terminal half of Tau). All phosphorylation sites were on Ser or Thr residues, but none on Tyr. Other known posttranslational modifications of Tau were near or below our detection limit (e.g. acetylation, ubiquitination).

2020-11-20 | PXD020985 | Pride

Bassoon contributes to tau-seed neurotoxicity and propagation.

Project description:Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. Growing evidence suggests that soluble tau aggregates trigger neurodegenerative phenotypes. However, the nature of the tau species and interactors involved in its aggregation and spreading remains unclear. By using size exclusion chromatography, mass spectrometry, and bioinformatic analysis, we identified Bassoon protein (BSN) as a significant tau interactor in PS19 mice, as well as in human AD and PSP cases. We also found that overexpression of BSN triggers the aggregation of tau and increase the tau seeding activity in vitro, and also exacerbates the degenerative phenotype in a Fly model for tauopathy. Knockdown of BSN significantly reduced tau spreading in PS19 mouse brains and destabilized the tau aggregates, leading to a reduction in the tau pathology in this model. Furthermore, BSN downregulation was able to restore the neurodegenerative phenotype in PS19 mice, observed in electrophysiology and behavioral tests. Our results identify BSN as a key interactor of tau spread and aggregation in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

2023-03-11 | PXD027451 | Pride

Physiological tau interactome in brain and its link to tauopathies_complete submission

Project description:Alzheimer's disease (AD) and most of other tauopathies are incurable neurodegenerative diseases with unpleasant symptoms and consequences. The common hallmark of all these diseases is tau pathology but its connection with disease progress has not been completely understood so far. Therefore, uncovering novel tau interacting partners and pathology affected molecular pathways can reveal the causes of diseases as well as potential targets for development of AD treatment. Despite of large amount of known tau interacting partners, limited number of studies focused on in vivo tau interactions in disease or healthy conditions are available. Here, we applied an in vivo crosslinking approach, capable of capturing weak and transient protein-protein interactions, to a unique transgenic rat model of progressive tau pathology similar to human AD. We have identified 175 potential novel and known tau interacting proteins by MALDI-TOF mass spectrometry. Several of the most promising candidates for potential drug development were selected for validation by coimmunoprecipitation and colocalization experiments in animal and cellular models.

2020-05-07 | PXD018687 | 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

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