Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Tauopathy

SUBMITTER: Didier Vertommen

LAB HEAD: Bernard J. Hanseeuw

PROVIDER: PXD038901 | Pride | 2023-06-22

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Are Mouse Models a surrogate for human disease? A temporal, quantitative and molecular perspective.

Project description:It is unclear to what extent Tau molecular pathology in murine models reflect human Tauopathies. Nevertheless, mouse models that overexpress human mutant Tau (P301S and P301L) are widely used in studies of Tauopathies and Alzheimer’s Disease (AD). In this study, we perform an in-depth temporally and spatially resolved mass spectrometry-based proteomic analysis of P301S (hTau.P301S) and P301L (rTg(tauP301L)4510) mice as well as human patients with AD or frontotemporal dementia due to the P301L mutation, to identify differences and similarities between human AD, animal models and human P301L patients. Both mouse models and human P301L patients show progressive Tau accumulation driven by Tau phosphorylation during disease progression as also observed in early human AD. However, Tau ubiquitination and acetylation, important in human AD, are less or not represented in the mouse models or in P301L patients. Our analyses provide guidance regarding designing mechanistic studies and testing of Tau directed therapeutics.

2023-02-03 | PXD033965 | Pride

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

Human tau 0N4R isoform hyperphosphorylation LC-MS/MS

Project description:Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3betaor stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites.

2022-04-13 | PXD033127 | Pride

Quantitative proteomics of tau and Aβ amyloid in detergent insoluble fractions from Alzheimer’s disease brains

Project description:The two hallmarks of Alzheimer’s disease (AD) are A-amyloid- (A) plaques and neurofibrillary tangles marked by phosphorylated tau. There is compelling evidence that aggregating A drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely there is a growing realization that non-fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Using quantitative proteomics, we find that AD brain sarkosyl-insoluble pellets are greatly enriched with A at almost equimolar levels to N-terminal truncated microtubule binding region (MTBR) isoforms of tau with multiple post-translational modifications (PTMs). The extracted R3-R4 tau peptides are 100-fold higher compared to N-terminus intact tau peptides. Substantial proportions of site-specific phosphorylation at T181 (~ 22 %) and T217 (~ 16 %) along with other PTMs in the proline rich region (PRR) and MTBR indicate a regional susceptibility of PTMs in aggregated tau. Immuno-electron microscopy reveals that co-purified A and tau co-localize to globular non-filamentous aggregates.

2022-06-04 | PXD032372 | Pride

Posttranslational modifications mediate the structural diversity of tauopathy strains

Project description:Tau aggregation is the defining pathological hallmark of tauopathies, but structural insights are revealing key differences between filaments across this class of disorders. Using cryo-electron microscopy, we identify a 107-residue fragment, K274-E380, which forms the insoluble core of tau filaments in the tauopathy corticobasal degeneration (CBD). This tau conformer is distinct from those identified in Alzheimer’s Disease (AD), Pick’s Disease, and Chronic Traumatic Encephalopathy, pointing towards a “one strain per disease” paradigm. Each disease-specific conformer can pack into multiple fibril subtypes and, despite similarities in secondary structure elements between tau filaments from CBD and AD, mass spectrometry revealed key differences in posttranslational modifications (PTMs). Given the abundance of lysine residues in the insoluble tau filament core in both CBD and AD, ubiquitination and acetylation are identified as key PTMs that compete to modify specific residues, which may ultimately determine filament morphology.

2020-02-14 | PXD016862 | 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

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

Tau posttranslational modifications

Project description:Human tauopathies including Alzheimer's disease are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. We immunoprecipitated Tau from post-mortem brain tissue of early stage Alzheimer's disease patients and age-matched controls, and analyzed PTMs on this soluble pool of Tau protein. In addition to known serine, threonine and tyrosine phosphorylation events, we identified a number of previously unknown monomethylation events on lysines in both control and Alzheimer's patient tissues.

2021-09-09 | PXD017065 | Pride

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

Quantitative proteomics of tau and Aβ amyloid in detergent insoluble fractions from Alzheimer’s disease brains

2022-06-04 | PXD032389 | 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