Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy
Kathy L. Newell,
Alexey G. Murzin,
Holly J. Garringer,
Sjors H.W. Scheres
Posted 21 Oct 2019
bioRxiv DOI: 10.1101/811703
Posted 21 Oct 2019
Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances. A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls and genome-wide association studies have identified additional risk factors. By histology, astrocytic plaques are diagnostic of CBD, as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE. Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R). 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 filaments. 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 CTE. 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.
- Downloaded 1,524 times
- Download rankings, all-time:
- Site-wide: 5,670 out of 88,669
- In neuroscience: 839 out of 15,782
- Year to date:
- Site-wide: 2,663 out of 88,669
- Since beginning of last month:
- Site-wide: 14,631 out of 88,669
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!