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FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau filaments.


ABSTRACT: Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive Tau in recipient cells into a pathological state, followed by assembly of pathological Tau fibers, similar to the mechanism of nucleated polymerization proposed for prion pathogenesis. In cell cultures, the process is often monitored by a FRET assay where the recipient cell expresses the Tau repeat domain (TauRD) with a pro-aggregant mutation, fused to GFP-based FRET pairs. Since the size of the reporter GFP (barrel of ~?3?nm?×?4?nm) is ~?7 times larger than the ?-strand distance (0.47?nm), this points to a potential steric clash. Hence, we investigated the influence of the GFP tag on TauFL or TauRD aggregation. Using biophysical methods (light scattering, atomic force microscopy (AFM), and scanning-transmission electron microscopy (STEM)), we found that the assembly of TauRD-GFP was severely inhibited and incompatible with that of Alzheimer filaments. These observations argue against the hypothesis that the propagation of Tau pathology in AD is caused by the prion-like templated aggregation of Tau protein, transmitted via cell-to-cell spreading of Tau. Thus, even though the observed local increase of FRET in recipient cells may be a valid hallmark of a pathological reaction, our data argue that it is caused by a process distinct from assembly of TauRD filaments.

SUBMITTER: Kaniyappan S 

PROVIDER: S-EPMC7364478 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau filaments.

Kaniyappan Senthilvelrajan S   Tepper Katharina K   Biernat Jacek J   Chandupatla Ram Reddy RR   Hübschmann Sabrina S   Irsen Stephan S   Bicher Sandra S   Klatt Christoph C   Mandelkow Eva-Maria EM   Mandelkow Eckhard E  

Molecular neurodegeneration 20200716 1


Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive Tau in recipient cells into a pathological state, followed by assembly of pathological Tau fibers, similar to the mechanism of nucleated polymerization  ...[more]

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