Takeshi Ikeuchi, Japan
Niigata University, Brain Research Institute Department of Molecular GeneticsAuthor Of 1 Presentation
NOVEL TAU FILAMENT FOLD IN CORTICOBASAL DEGENERATION, A FOUR-REPEAT TAUOPATHY
Abstract
Aims
Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterized by motor and cognitive disturbances. By histology, astrocytic plaques are diagnostic of CBD; by SDS–PAGE, so too are detergent-insoluble, 37 kDa fragments of tau. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats. This distinguishes such ‘4R’ tauopathies from Pick’s disease (3R tauopathies) and from Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) (3R+4R tauopathies). We previously reported different tau filament structures from AD, Pick’s disease and CTE, but tau filament structures of 4R tauopathies remained unknown.
Methods
We extracted the tau filaments from the brains of three individuals with CBD and used cryo-electron microscopy to analyse the structures of the tau filaments.
Results
These filaments from CBD were identical between cases, but distinct from those seen in AD, Pick’s disease and CTE. The core of a CBD filament comprises residues 274 to 380 of tau, spanning the last residue of the R1 repeat, all of the R2, R3 and R4 repeat, and 12 residues after R4 repeat. 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.
Conclusions
Our determination of the CBD fold opens up 4R tauopathies to structural analysis. It supports the hypothesis that distinct conformers of filamentous tau define different tauopathies.