Abstract
The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 Tau variants for their ability to be seeded by exogenous Tau fibrils. Our findings revealed stark differences between FTDP-17 Tau variants in their ability to be seeded, with variants at Pro301 and Ser320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain Tau protein regions and unique residues, including the role of Pro301 in inhibiting Tau aggregation. We also revealed potential barriers in cross-seeding between three-repeat and four-repeat Tau isoforms. Overall, these differences alluded to potential mechanistic differences between wildtype and FTDP-17 Tau variants, as well as different Tau isoforms, in influencing Tau aggregation. Furthermore, by combining two FTDP-17 Tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that do not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate Tau aggregation without the need for exogenous Tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate Tau aggregation.
Highlights
The accumulation of aberrantly aggregated MAPT defines a spectrum of tauopathies, including Alzheimer’s disease
P301L and P301S Tau showed similar amounts of aggregation, whereas S320F Tau aggregated to a lesser extent
In the absence of WT K18 fibrils, S320F Tau transfected cells displayed a small amount of self-aggregation (p Ͻ 0.01), which was not observed for the other mutants or WT Tau (Fig. 2, A and C)
Summary
Ing evidence supports prion-like seeding as a mechanism in the spread of Tau pathology [25,26,27]. Even within the proposed mechanism of conformational templating and seeding, the spontaneous aggregation of Tau monomer to Tau “seed” must first take place. This transition involves the stacking of -sheeted Tau into fibrillar “amyloid” Tau, which are the basis of larger Tau inclusions [36]. We examined the intrinsic propensity of a large array of FTDP-17 Tau mutants to be induced to aggregate when exogenously seeded in cultured cells. We assessed the seeding outcomes of additional synthetic mutants in close proximity to regions of structural interest to inform on the importance of specific motifs in regulating Tau aggregation. Our data show sharp differences in the ability for WT and most FTDP-17 Tau mutants to be seeded ex vivo when compared with mutants at Pro301 or Ser320, indicating that specific residues/regions within Tau are critical in modulating aggregation and seeding, highlighting novel targets for Tau therapeutics
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