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Novel tau filament fold in corticobasal degeneration


Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances1–3. A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls4,5 and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8, as are detergent-insoluble tau fragments of 37 kDa by SDS–PAGE9. Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD)10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R)11–15. This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments16. Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE17–19. The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

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Correspondence to Michel Goedert or Sjors H. W. Scheres.

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Supplementary Figure 1

This file contains source images for Western blots. (a), Source images for Western blots shown in Fig. 1g. (b), Source images for Western blots shown in Extended_Data_Fig. 3. (c) Source images for Western blots shown in Extended_Data_Figure 8a.

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Zhang, W., Tarutani, A., Newell, K.L. et al. Novel tau filament fold in corticobasal degeneration. Nature (2020).

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