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

• Published in: Acta neuropathologica Vol. 139; no. 6; pp. 1045 - 1070
• Main 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
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2020; Springer; Springer Nature B.V
• Subjects: Aged; Animals; Brain; Brain - pathology; Female; Frontotemporal dementia; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Gene mutations; Genetic aspects; Humans; Male; Medicine; Medicine & Public Health; Mice; Middle Aged; Monomers; Mutation; Mutation - genetics; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Phenotype; Phenotypes; Physiological aspects; Stochasticity; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - pathology; Therapeutic applications; Transgenic mice; Aging/P301L mutation; Transgenic mouse; Strain ensembles; Tauopathy; Seeding; Focal pathology; Conformation
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-020-02148-4

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 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.