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Ubiquitination of protein Tau in Alzheimer's disease

ABSTRACT: Identification of posttranlational modifications of Tau in Alzheimer's disease

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Yingxin Zhao

LAB HEAD: Yingxin Zhao, Ph.D.

PROVIDER: PXD031417 | Pride | 2022-05-19

REPOSITORIES: Pride

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			Action	DRS
	AD-Tau1.raw	Raw
	AD-Tau2.raw	Raw
	checksum.txt	Txt
	txt.zip	Other

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Publications

Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer's disease.

Puangmalai Nicha N Sengupta Urmi U Bhatt Nemil N Gaikwad Sagar S Montalbano Mauro M Bhuyan Arijit A Garcia Stephanie S McAllen Salome S Sonawane Minal M Jerez Cynthia C Zhao Yingxin Y Kayed Rakez R

The Journal of biological chemistry 20220222 4

Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observed that K63-linked, but not K48-linked, ubiquitinated TauO accumulated at higher levels in AD brains compared with age-matched controls ...[more]

PMID: 35202653

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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

Quantitative PTM Maps of Human Pathologic Tau Identify Patient Heterogeneity and Define Critical Steps in Alzheimer’s Disease Progression - high/low molecular weight tau

Project description:To elucidate the role of Tau isoforms and PTM stoichiometry in Alzheimer’s disease (AD), we generated a high resolution quantitative proteomic map of 88 PTMs on multiple isoforms of Tau isolated from the post-mortem human tissue from 49 AD and 42 control subjects. While Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and patient frequency for AD suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by the analysis of size fractionated Tau. To summarize, critical features within the Tau protein for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C-terminal, an increase in negative charge in the PRR and a decrease in positive charge in the MBD.

2020-12-04 | PXD020483 | Pride

Synaptosomal microRNAs and Alzheimer's disease

Project description:Purpose of our study is to determine the status of synaptosomal microRNAs in Alzheimer's disease and their roles in Alzheimer's progression.

2022-08-01 | E-MTAB-11983 | 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

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RNAseq in Alzheimer's Disease patients

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

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2023-06-22 | PXD038901 | 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

nELAVL HITS-CLIP in Alzheimer's Disease patients

Project description:Human brain samples from control and advanced Alzheimer's Diseased subjects were subjected to HITS-CLIP to monitor nELAVL binding changes during AD progression Human brain samples were obtained from the Mount Sinai Brain Bank; samples were UV-irradiated and subjected to nELAVL HITS-CLIP (detailed desription in accompanying paper)

2016-02-17 | E-GEOD-53695 | biostudies-arrayexpress

Cerebellum Alzheimer's Disease

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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