The existence of distinct tau filament folds in different human tauopathies has been established in a new study published in Nature. Visualization and atomic modelling of tau filaments in Pick disease revealed a distinct protein structure from that observed in Alzheimer disease (AD).
Tau filaments are hallmarks of AD and Pick disease, but they are made up of different tau isoforms in the two diseases. Filaments in Pick disease contain only tau isoforms with three microtubule-binding repeats (3R tau), whereas filaments in AD also contain tau with four repeats (4R tau). However, the structural reasons for these differences have been unclear.
Now, Michel Goedert, Sjors Scheres and colleagues at the Medical Research Council Laboratory of Molecular Biology, UK, together with collaborators at the Indiana University School of Medicine, USA, have used cryo-electron microscopy (cryo-EM) to provide new insight. “Last year, we reported the high-resolution structures of tau filaments from the AD brain,” explains Goedert. “We now report the high-resolution structures of tau filaments from the Pick disease brain.”
The researchers isolated tau filaments from the frontotemporal cortex of a person who had Pick disease and visualized these filaments with cryo-EM to determine the structures of their ordered cores. “Cryo-EM is the only available technique to solve structures of ex vivo amyloid filaments, which are not likely to crystallize and cannot be labelled with isotopes for nuclear magnetic resonance,” says Scheres.
The cryo-EM structures showed that tau protein folds differently between Pick disease and AD. Furthermore, an atomic model of the Pick tau filament fold revealed that the tau structure adopted in Pick disease causes physical constraints that exclude the second microtubule-binding repeat that is present in 4R tau. This observation explains why Pick disease-associated filaments only contain 3R tau.
“Different molecular conformers of aggregated tau distinguish Pick disease from AD, and may explain why they are distinct clinical and neuropathological diseases,” says Goedert.
Different molecular conformers of aggregated tau distinguish Pick disease from AD
The researchers say that we now need to know the atomic structures of tau filaments in other tauopathies, including those that involve only 4R tau. “Ultimately, this work may tell us something about how soluble tau protein assembles into a variety of different filament structures,” says Goedert. “This may well have therapeutic consequences.”
Change history
09 October 2018
In the original version of this article published online, Michel Goedert’s first name was spelt incorrectly and the affiliation of Sjors Scheres was incorrect. These errors have been corrected in the HTML and PDF versions of the article.
References
Original article
Falcon, B. et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature https://doi.org/10.1038/s41586-018-0454-y (2018)
Further reading
Polanco, J. C. et al. Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14, 22–39 (2017)
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Fyfe, I. Tau folds differently between diseases. Nat Rev Neurol 14, 633 (2018). https://doi.org/10.1038/s41582-018-0076-x
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DOI: https://doi.org/10.1038/s41582-018-0076-x