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

Molecular Neurodegeneration
Senthilvelrajan KaniyappanEckhard Mandelkow

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 β-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 ...Continue Reading

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Citations

Apr 9, 2021·Frontiers in Neuroscience·Aurelien Lathuiliere, Bradley T Hyman
Apr 24, 2021·Current Opinion in Neurobiology·Susanne WegmannEckhard Mandelkow
Mar 12, 2021·Brain : a Journal of Neurology·Airi TarutaniMasato Hasegawa
Sep 1, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Emily MiyoshiKaren Hoppens Gylys
Aug 11, 2021·Chembiochem : a European Journal of Chemical Biology·Marwa MalhisSusanne Aileen Funke
Nov 9, 2021·The Journal of Physical Chemistry Letters·Siddhartha Banerjee, Ayanjeet Ghosh

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Methods Mentioned

BETA
FRET
AFM
PCR
gel filtration
light scattering
transmission electron microscopy
light
fluorescence microscopy
UV light scattering
atomic force microscopy

Software Mentioned

JPK
PCMASS32

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