Pathological aggregation of the microtubule-associated protein tau is the underlying cause of several neurodegenerative diseases. These ‘tauopathies’ have very diverse neuronal phenotypes and clinical manifestations. How tau aggregation gives rise to such varied phenotypes is unclear, but it has been recently hypothesized that differently folded forms of abnormal tau might be associated with different tauopathies. Reporting in Cell, Arakhamia et al. now find that tau post-translational modifications (PTMs) and their crosstalk contribute to the formation of disease-specific intracellular tau aggregates.
Previous studies have reported several tau PTMs — which might enable tau to acquire highly ordered β-sheet structures that facilitate tau aggregation and the formation of pathological filamentous inclusions — but these modifications had not been identified in structural studies, because the treatment of tissue-derived tau removes the PTMs. Here, the authors were able to solve the structures of post-translationally modified tau filaments isolated from the brains of individuals with corticobasal degeneration (CBD) or Alzheimer disease (AD) by using a combination of cryo-electron microscopy (EM) and mass spectrometry (MS)-based proteomics.
The authors analysed densely-packed, insoluble tau inclusions from patients with CDB and AD, which they found to form both straight and twisted filaments, and mapped the positions of four types of PTM — acetylation, ubiquitylation, methylation and phosphorylation. Whereas some were common to CBD and AD, the majority were distinct. Interestingly, when comparing the CBD and AD filaments, they found that although the β-strand-forming motifs in the two diseases are highly similar, the misfolding of individual tau molecules and their self-assembly into fibrils is different.
“ubiquitin incorporated into tau filaments in CBD and AD mediates specific inter-protofilament packing”
On the basis of the analyses of ubiquitylation sites, localized in the atomic models, the authors propose that ubiquitin incorporated into tau filaments in CBD and AD mediates specific inter-protofilament packing. Ubiquitin chains may provide additional contacts between tau molecules, favouring the formation and stabilization of fibril subtypes that are specific to the disease. Thus, the approach of combining cryo-EM with MS-based proteomics has the potential to reveal the role of PTMs in the onset and development of neurodegenerative diseases.
Arakhamia, T. et al. Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell 180, 633–644 (2020)
About this article
Cite this article
Baumann, K. Tau intricacies in disease. Nat Rev Mol Cell Biol 21, 180 (2020). https://doi.org/10.1038/s41580-020-0233-0