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 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.

Tau Conformers in FTLD-MAPT  Undergo Liquid-liquid Phase Separation and Perturb the Nuclear Envelope

“…Our resources included brain tissue from ten Iberian FTLD-MAPT-P301L patients [34], that likely derive from a common ancestor [47]. These P301L cases characterized previously for tau pathology and con rmed the absence of confounding proteinopathies [5,34], were augmented by a number of controls including Alzheimer's disease cases, frontotemporal dementia with progranulin mutations, amyotrophic lateral sclerosis cases and non-demented controls. Although analyses by others have remarked upon nuclear clefts as a feature of FTLD-MAPT [18], when examining the nuclei of dentate gyrus neurons this nding also applied to other clinical entities, being abundant within three amyotrophic lateral sclerosis cases, two progranulin mutation carriers and in one non-demented control ( Table 1, Fig.…”

“…Clinical features of the patients were assessed as per contemporaneous criteria for diagnosis [35,36]. Control brain samples were obtained from patients who died from non-neurological diseases; diagnostic neuropathology and retrospective chart reviews were carried out for all subjects, with particular attention to ruling out other age-related neurodegenerative diseases as previously described [5]. TgTau P301L mice samples were obtained as described previously [5,37,38].…”

“…Control brain samples were obtained from patients who died from non-neurological diseases; diagnostic neuropathology and retrospective chart reviews were carried out for all subjects, with particular attention to ruling out other age-related neurodegenerative diseases as previously described [5]. TgTau P301L mice samples were obtained as described previously [5,37,38]. All animal experiments were performed in accordance with local and Canadian Council on Animal Care ethics guidelines.…”

“…The reporter cells were seeded as previously described [5,38]. Brie y, tau reporter cells were plated at 1x10 6 cells/well of a 12-well culture plates and, on the next day, seeded with liposome-protein complexes derived from S1 brain fractions of TgTau P301L mice presenting with signs of neurological disease (as described previously [38,41]).…”

“…The conformational change of monomeric soluble tau into other conformers that include hyperphosphorylated oligomers, paired helical laments and brillized tau is thought to contribute to neuronal toxicity and cell death [1][2][3]. We recently reported that even the same germline mutation, MAPT-P301L, generates distinct tau conformers as appraised by conformation-dependent immunoassay and conformational stability assays (CSAs) [5]. The diverse and evolving repertoire of tau conformers that includes four CSA pro les in mice (CSA Types 1-4) was postulated as the origin of neuropathological and biochemical heterogeneity of FTLD with tau immunoreactive inclusions (FTLD-tau) [1,5].…”