Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

Xiang, X.; Arakhamia, T.; Carlomagno, Y.; Dhingra, S.; Thierry, M.; DeTure, M.; Cook, C. N.; Dickson, D. W.; Petrucelli, L.; Fitzpatrick, A.

doi:10.1101/2021.05.24.445353

bioRxiv · 10.1101/2021.05.24.445353

Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

Xiang, X.·Arakhamia, T.·Carlomagno, Y.·Dhingra, S.·Thierry, M.·DeTure, M.·Cook, C. N.·Dickson, D. W.·Petrucelli, L.·Fitzpatrick, A.

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Abstract

Misfolding and aggregation of tau protein is implicated in many neurodegenerative diseases that are typified by the presence of large, filamentous tau inclusions. The aggregation of tau in human brain is disease-specific with characteristic filaments defining the neuropathology. An understanding of how identical tau isoforms aggregate into disparate filament morphologies in phenotypically distinct tau-related diseases remains elusive. Here, we determine the structure of a brain-derived twisted tau filament in progressive supranuclear palsy and compare it to a dissimilar tau fold found in corticobasal degeneration. While the tau filament core in both diseases is comprised of residues 274 to 380, molecular-level polymorphism exists. Potential origins of the molecular polymorphism, such as noncovalent cofactor binding, are identified and predicted to modulate tau filament structures in the brain.

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Xiang, X., Arakhamia, T., Carlomagno, Y., Dhingra, S., Thierry, M., DeTure, M., Cook, C. N., Dickson, D. W., Petrucelli, L., Fitzpatrick, A.. 2021-05-25. Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases. https://doi.org/10.1101/2021.05.24.445353

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