Novel tau filament fold in corticobasal degeneration

Wenjuan Zhang, Airi Tarutani, Kathy L. Newell, Alexey G. Murzin, Tomoyasu Matsubara, Benjamin Falcon, Ruben Vidal, Holly J. Garringer, Yang Shi, Takeshi Ikeuchi, Shigeo Murayama, Bernardino Ghetti, Masato Hasegawa, Michel Goedert () and Sjors H. W. Scheres ()
Additional contact information
Wenjuan Zhang: MRC Laboratory of Molecular Biology
Airi Tarutani: Tokyo Metropolitan Institute of Medical Science
Kathy L. Newell: Indiana University School of Medicine
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Tomoyasu Matsubara: Tokyo Metropolitan Institute of Gerontology
Benjamin Falcon: MRC Laboratory of Molecular Biology
Ruben Vidal: Indiana University School of Medicine
Holly J. Garringer: Indiana University School of Medicine
Yang Shi: MRC Laboratory of Molecular Biology
Takeshi Ikeuchi: Niigata University
Shigeo Murayama: Tokyo Metropolitan Institute of Gerontology
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, 2020, vol. 580, issue 7802, 283-287

Abstract: Abstract Corticobasal degeneration (CBD) is a neurodegenerative tauopathy—a class of disorders in which the tau protein forms insoluble inclusions in the brain—that is characterized by motor and cognitive disturbances1–3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS–PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11–15. This distinguishes such ‘4R’ tauopathies from Pick’s disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer’s disease, Pick’s disease and CTE17–19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

Date: 2020
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DOI: 10.1038/s41586-020-2043-0

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