Neurology and Neurosurgery

Oct. 02, 2020

Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation of structures in disease-specific tauopathies. Structural studies have failed to pinpoint changes associated with an individual tauopathy, likely due to the methods used to evaluate tau filaments.

With collaborators from Columbia University and Emory University School of Medicine, Mayo Clinic researchers used a new method combining cryoelectron microscopy and mass spectrometry-based proteomics. Applying that method to human tissue samples from the Mayo Clinic brain bank, the researchers identified post-translational modifications as playing an important role in mediating the distinct structures of tau fibrils in corticobasal degeneration and Alzheimer's disease.

Comparisons of the structures of post-translationally modified tau filaments in the two neurodegenerative conditions showed many common structural elements as well as both shared and distinct post-translational modifications. Although the beta strand-forming motifs in the two diseases are highly similar, their misfolding and self-assembly into fibrils are radically different.

The researchers propose a structure-based model in which cross-talk between post-translational modifications influences tau filament structure and behavior, contributing to the structural diversity of tauopathy strains. The researchers further propose that their approach of combining cryoelectron microscopy and mass spectrometry-based proteomics forms a methodological blueprint to fully decipher the role of post-translational modifications in neurodegeneration.

Study results were published in Cell in 2020.

For more information

Arakhamia T, et al. Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell. 2020;180:633.