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Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains.

ABSTRACT: 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 posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer's disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease.

SUBMITTER: Arakhamia T

PROVIDER: S-EPMC7491959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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

Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice.

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