Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation.

ABSTRACT: Tau protein accumulation is a common denominator of major dementias, but this process is inhomogeneous, even when triggered by the same germline mutation. We considered stochastic misfolding of human tau conformers followed by templated conversion of native monomers as an underlying mechanism and derived sensitive conformational assays to test this concept. Assessments of brains from aged TgTau^P301L transgenic mice revealed a prodromal state and three distinct signatures for misfolded tau. Frontotemporal lobar degeneration (FTLD)-MAPT-P301L patients with different clinical phenotypes also displayed three signatures, two resembling those found in TgTau^P301L mice. As physicochemical and cell bioassays confirmed diverse tau strains in the mouse and human brain series, we

SUBMITTER: Daude N 

PROVIDER: S-EPMC7244472 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature