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Tau interactome - The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the P301L mutant to chaperones and the proteasome

ABSTRACT: The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer’s disease, a subset of frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet the proteins it interacts with have not been studied using a systematic discovery approach. The study employed mild in vivo crosslinking, isobaric labeling and tandem mass spectrometry to characterize molecular interactions of human tau in a neuroblastoma cell model.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Neuroblast

DISEASE(S): Alzheimer's Disease

SUBMITTER: Gerold Schmitt-Ulms

LAB HEAD: Gerold Schmitt-Ulms

PROVIDER: PXD002058 | Pride | 2015-08-17

REPOSITORIES: Pride

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The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome.

Gunawardana C Geeth CG Mehrabian Mohadeseh M Wang Xinzhu X Mueller Iris I Lubambo Isabela B IB Jonkman James E N JE Wang Hansen H Schmitt-Ulms Gerold G

Molecular & cellular proteomics : MCP 20150811 11

The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer's disease, a subset of frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet the proteins it interacts with have not been studied using a systematic discovery approach. Here we employed mild in vivo crosslinking, isobaric labeling, and tandem mass spectrometry to characterize molecular interactions of human tau in a neuroblastoma cell model. ...[more]

PMID: 26269332

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Neuronal interactome changes upon aggregation of Tau

Project description:To understand at molecular level how aggregation of Tau modulates its interactions with proteins we reveal key determinant for derailing Tau protein network. By performing quantitative AP-MS we define a new set of interactors which bind Tau upon fibril formation. These interactors contain disordered regions with a unique amino acidic footprint. Such regions are enriched in positively charged Arginines which can engage aberrant binding to Tau fibrils through their guanidinium group via pi-stacking. We also find that the Hsp90 chaperone stalls formation of Tau fibrils and reshapes their abnormal interactome.

2020-01-30 | PXD015432 | 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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2019-01-09 | PXD009294 | Pride

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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.

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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

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Zeugodacus tau

Project description:Zeugodacus tau overview

| PRJNA492538 | ENA

Quantitative PTM Maps of Human Pathologic Tau Identify Patient Heterogeneity and Define Critical Steps in Alzheimer’s Disease Progression - angular gyrus

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Project description:One of the defining pathological features of Alzheimer’s Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

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