Dataset Information

Posttranslational modifications mediate the structural diversity of tauopathy strains

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Duc Duong

LAB HEAD: Nicholas Seyfried

PROVIDER: PXD016862 | Pride | 2020-02-14

REPOSITORIES: Pride

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Publications

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains.

Arakhamia Tamta T Lee Christina E CE Carlomagno Yari Y Duong Duc M DM Kundinger Sean R SR Wang Kevin K Williams Dewight D DeTure Michael M Dickson Dennis W DW Cook Casey N CN Seyfried Nicholas T NT Petrucelli Leonard L Fitzpatrick Anthony W P AWP

Cell 20200206 4

Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with p ...[more]

PMID: 32032505

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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.

Dataset Information

Posttranslational modifications mediate the structural diversity of tauopathy strains

Publications

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains.

Similar Datasets

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