How local sequence propensity shapes amyloid polymorphism of tau

In this paper we investigated the intrinsic structural factors contributing to the polymorphism of tau amyloid fibrils, which are linked to neurodegenerative disorders known as tauopathies. We identified a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), within the tau protein, which significantly contributes to the polymorphic nature of tau fibrils by using a combination of cryo-electron microscopy (cryo-EM), in-cell experiments, and biophysical analyses to understand the role of PAM4. We showed that PAM4 adopts various structures that closely resemble those found in different disease-associated tau strains and that deletion of PAM4 impaired the cellular seeding efficiency of tau aggregates from Alzheimer’s disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) patients, underscoring PAM4’s crucial role in these tauopathies.

These findings highlight that the intrinsic structural propensities of amyloid core segments, particularly PAM4, are key in determining tau fibril structures and their propagation in cells. This research provides insights into how tau polymorphism is shaped by both intrinsic structural factors and disease-specific conditions, and may inform future therapeutic strategies for tauopathies.

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