Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis**

Abstract

Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well-characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single-molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tau-RD 244-368 ). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro-amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti-amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau-RD 244-368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.

Modulation of Primary and Secondary Processes in Tau Fibril Formation by Salt-Induced Dynamics

“…This similarity confirms that salt decreases the relaxation rate and increases the dynamics, which leads to the formation of AD and CTE-like filaments. The increased dynamics apparently favor the formation of aggregation-prone conformers leading to the particular structure . A similar observation was noted for α-synuclein where the effect of salt on the dynamics and aggregation was reported …”

Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM

“…The structural differences in fibrils from the heart and the eye could be driven by at least three factors: the local environment of the deposition site, the local environment of the media in where transthyretin circulates, or protein changes made before secretion by its source (this is, the liver or the retina epithelium, respectively). The importance of the local environment in an amyloid protein to acquire different fibril morphologies has already been reported for tau (Lövestam et al, 2022), modulating the first structural rearrangement of the monomer prior to aggregation (Fernández-Ramírez et al, 2023). These structural rearrangements could occur while the protein is in circulation or at the deposition site.…”