Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

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 t...Continue Reading