Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tau Protein Modulates an Epigenetic Mechanism of Cellular Senescence in Human SH-SY5Y Neuroblastoma Cells

ABSTRACT: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation. To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells. Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells. Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242694 | GEO | 2023/09/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Distinct amyloid-b and tau associated microglia profiles in Alzheimer's disease

Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

2021-02-20 | GSE148822 | GEO

RNA-Seq of human primary microglial cells treated with vehicle or human paired helical filaments (PHFs) purified from human tauopathy autopsy brain

Project description:Neuroinflammation is one of the major neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia often co-exist in the same brain regions where tau protein accumulates as hyperphosphorylated and aggregated PHFs or neurofibrillary tangles (NFTs) within neurons in patients with AD and related tauopathies. However, the exact mechanisms how pathological tau could induce neuroinflammatory responses are not clear. In this study, we treated primary human microglia with purified human PHFs and performed RNA-sequence analysis.

2021-09-16 | E-MTAB-5742 | biostudies-arrayexpress

Increased G3BP2-Tau interaction in Tauopathies is a natural defense against Tau aggregation

Project description:Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies.

2023-05-17 | GSE226624 | GEO

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

Specific post-translational modifications of the soluble tau protein distinguish between Alzheimer’s disease, 4R-, and 3R-tauopathies

Project description:The tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The type of tau isoforms (4R/3R) observed in brain aggregates is used to classify tauopathies. However, distinguishing tauopathies in cerebrospinal fluid remains challenging. Here, we demonstrated that the difference in tau isoforms between tauopathies is only observed in aggregates, not in soluble brain extracts. We therefore used untargeted mass spectrometry to characterize all post-translational modifications of both the aggregated and the soluble tau protein obtained from human brain tissue of patients with Alzheimer’s disease, cortico-basal degeneration, Pick’s disease, and fronto-temporal lobe degeneration. We found specific soluble signatures predictive of each tauopathy and its peculiar type of aggregated tau isoforms. These findings provide potential targets for developing cerebrospinal fluid assays able to distinguish between tauopathies in vivo. The comparison between soluble and aggregated tau features indicates potential mechanisms of tau aggregation, providing novel therapeutic leads for these diseases

2023-06-22 | PXD038901 | Pride

DIA-MS Detect the Dephosphorylation of Tau by Phosphorylation Targeting Chimera (PhosTAC)

Project description:Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimer’s disease and other tauopathies, one of the greatest unmet demands in the clinic. In vivo studies using kinase inhibitors suggest that reducing tau phosphorylation levels has therapeutic potential; however, such approaches invariably showed limited benefits. We sought to develop our recently demonstrated Phosphorylation Targeting Chimera (PhosTAC) technology to specifically induce tau dephosphorylation. Herein, we use PhosTACs to recruit tau to PP2A, a native tau phosphatase. PhosTACs induced the formation of a stable ternary complex, leading to a rapid, efficient, and sustained dephosphorylation of tau, which also correlated the enhanced down regulation of tau. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. We believe that PhosTACs present advantages over current strategies to modulate tau phosphorylation and represent a new avenue for disease-modifying therapies for tauopathies.

2023-03-16 | PXD037459 | Pride

Comparative gene expression profiling of Drosophila primary neuronal cultures expressing or not the human Tau0N4RWT protein

Project description:Deciphering the pathophysiological mechanisms that lead from the alteration of human Tau biology to neuronal death in tauopathies including Alzheimer's disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) depends notably on the identification of Tau cellular partners and a better understanding of Tau functions. In this aim, we performed gene expression profiling to identify upregulated and downregulated genes in response to ectopic induced expression for 3 days of human Tau0N4RWT protein in Drosophila primary neuronal cultures from Elav-GAL4GS larval brains.

2020-02-11 | E-MTAB-8712 | biostudies-arrayexpress

Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies III

Project description:Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

2022-08-07 | GSE209747 | GEO

Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies II

2022-08-04 | GSE204931 | GEO

Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies I

2022-08-04 | GSE204930 | GEO