Structure-based classification of tauopathies.

Abstract

The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease1,2, Pick's disease3, chronic traumatic encephalopathy4 and corticobasal degeneration5 are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.

• Authors: Yang Shi, Wenjuan Zhang, Yang Yang, Alexey G Murzin, Benjamin Falcon, Abhay Kotecha, Mike van Beers, Airi Tarutani, Fuyuki Kametani, Holly J Garringer, Ruben Vidal, Grace I Hallinan, Tammaryn Lashley, Yuko Saito, Shigeo Murayama, Mari Yoshida, Hidetomo Tanaka, Akiyoshi Kakita, Takeshi Ikeuchi, Andrew C Robinson, David M A Mann, Gabor G Kovacs, Tamas Revesz, Bernardino Ghetti, Masato Hasegawa, Michel Goedert, Sjors H W Scheres
• Journal: Nature (Nature) Vol. 598 Issue 7880 Pg. 359-363 (10 2021) ISSN: 1476-4687 [Electronic] England
• PMID: 34588692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• MAPT protein, human
• Protein Isoforms
• tau Proteins

Topics

• Aged
• Aged, 80 and over
• Amino Acid Sequence
• Cryoelectron Microscopy
• Dementia (genetics)
• Denmark
• Female
• Humans
• Introns (genetics)
• Male
• Middle Aged
• Models, Molecular
• Mutation
• Protein Folding
• Protein Isoforms (chemistry, ultrastructure)
• Supranuclear Palsy, Progressive
• Tauopathies (classification, pathology)
• United Kingdom
• tau Proteins (chemistry, ultrastructure)