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- Title
Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation.
- Authors
Daude, Nathalie; Kim, Chae; Kang, Sang-Gyun; Eskandari-Sedighi, Ghazaleh; Haldiman, Tracy; Yang, Jing; Fleck, Shelaine C.; Gomez-Cardona, Erik; Han, Zhuang Zhuang; Borrego-Ecija, Sergi; Wohlgemuth, Serene; Julien, Olivier; Wille, Holger; Molina-Porcel, Laura; Gelpi, Ellen; Safar, Jiri G.; Westaway, David
- 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 TgTauP301L 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 TgTauP301L mice. As physicochemical and cell bioassays confirmed diverse tau strains in the mouse and human brain series, we conclude that evolution of diverse tau conformers is intrinsic to the pathogenesis of this uni-allelic form of tauopathy. In turn, effective therapeutic interventions in FTLD will need to address evolving repertoires of misfolded tau species rather than singular, static molecular targets.
- Subjects
FRONTOTEMPORAL lobar degeneration; NEUROFIBRILLARY tangles; TRANSGENIC mice; TAU proteins; PATHOLOGY; PHENOTYPES
- Publication
Acta Neuropathologica, 2020, Vol 139, Issue 6, p1045
- ISSN
0001-6322
- Publication type
Article
- DOI
10.1007/s00401-020-02148-4