Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation.
Acta Neuropathol
; 139(6): 1045-1070, 2020 06.
Article
in En
| MEDLINE
| ID: mdl-32219515
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tau Proteins
/
Frontotemporal Lobar Degeneration
Limits:
Aged
/
Animals
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Acta Neuropathol
Year:
2020
Document type:
Article
Affiliation country:
Canada