Distinct tau filament folds in human MAPT mutants P301L and P301T

Abstract

Mutations in MAPT, the tau gene, give rise to frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with abundant filamentous tau inclusions in brain cells. Mutations that encode missense variants of residue P301 are the most common and result in the formation of filamentous inclusions made of mutant four-repeat tau. Here we report the cryo-electron microscopy structures of tau filaments from five individuals belonging to three different families with mutation P301L and from one individual from a family with mutation P301T. A distinct three-lobed tau fold resembling the two-layered fold of Pick’s disease was present in the individuals with P301L tau. Two different tau folds were found in the individual with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. Schweighauser, Shi, Murzin and colleagues report cryo-EM structures of tau filaments from individuals with P301L or P301T MAPT mutations. P301L tau filaments adopted a distinct three-lobed fold, while P301T filaments had either a variant of the three-lobed fold or a V-shaped fold.