Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q TRAP, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Christoph Schlaffner

LAB HEAD: Judith A. Steen

PROVIDER: PXD020538 | Pride | 2020-12-04

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	AD02_BA46_INSOLUBLE_01.raw	Raw
	AD02_BA46_INSOLUBLE_01.wiff	Wiff
	AD02_BA46_INSOLUBLE_01.wiff.scan	Wiff
	AD02_BA46_INSOLUBLE_01_ACETYL_01.group	Other
	AD02_BA46_INSOLUBLE_01_PHOSPHO_01.group	Other

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Publications

Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease.

Wesseling Hendrik H Mair Waltraud W Kumar Mukesh M Schlaffner Christoph N CN Tang Shaojun S Beerepoot Pieter P Fatou Benoit B Guise Amanda J AJ Cheng Long L Takeda Shuko S Muntel Jan J Rotunno Melissa S MS Dujardin Simon S Davies Peter P Kosik Kenneth S KS Miller Bruce L BL Berretta Sabina S Hedreen John C JC Grinberg Lea T LT Seeley William W WW Hyman Bradley T BT Steen Hanno H Steen Judith A JA

Cell 20201113 6

To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in ...[more]

PMID: 33188775

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Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.