Structure-based classification of tauopathies

Yang Shi, Wenjuan Zhang, Yang Yang, Alexey G. Murzin, Benjamin Falcon, Abhay Kotecha, Mike 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 () and Sjors H. W. Scheres ()
Additional contact information
Yang Shi: MRC Laboratory of Molecular Biology
Wenjuan Zhang: MRC Laboratory of Molecular Biology
Yang Yang: MRC Laboratory of Molecular Biology
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Benjamin Falcon: MRC Laboratory of Molecular Biology
Abhay Kotecha: Thermo Fisher Scientific
Mike Beers: Thermo Fisher Scientific
Airi Tarutani: Tokyo Metropolitan Institute of Medical Science
Fuyuki Kametani: Tokyo Metropolitan Institute of Medical Science
Holly J. Garringer: Indiana University School of Medicine
Ruben Vidal: Indiana University School of Medicine
Grace I. Hallinan: Indiana University School of Medicine
Tammaryn Lashley: UCL Queen Square Institute of Neurology
Yuko Saito: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Shigeo Murayama: United Graduate School of Child Development, University of Osaka
Mari Yoshida: Aichi Medical University
Hidetomo Tanaka: Niigata University
Akiyoshi Kakita: Niigata University
Takeshi Ikeuchi: Niigata University
Andrew C. Robinson: University of Manchester, Salford Royal Foundation Trust
David M. A. Mann: University of Manchester, Salford Royal Foundation Trust
Gabor G. Kovacs: University of Toronto
Tamas Revesz: UCL Queen Square Institute of Neurology
Bernardino Ghetti: Indiana University School of Medicine
Masato Hasegawa: Tokyo Metropolitan Institute of Medical Science
Michel Goedert: MRC Laboratory of Molecular Biology
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology

Nature, 2021, vol. 598, issue 7880, 359-363

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03911-7

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