Water-directed pinning is key to tau prion formation

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tau protein aggregates are hallmarks of tauopathies, a group of neurodegenerative diseases.
• Synthetic replication of disease-specific tau fibril structures is essential for developing diagnostics and therapeutics.

Purpose of the Study:

• To identify a minimal folding motif in tau fibrils characteristic of tauopathies.
• To generate seeding-competent fibrils from isolated tau peptides for disease modeling.

Main Methods:

• Utilized a 19-residue tau peptide (jR2R3) containing the P301L mutation.
• Employed cryo-electron microscopy (cryo-EM) to determine fibril structure at 3 Å resolution.
• Investigated the role of the VQIVYK hexapeptide and SLS motif in fibril formation.

Main Results:

• The jR2R3 peptide with the P301L mutation forms prion-competent fibrils.
• The P301L mutation lowers aggregation barriers and facilitates in-register stacking via pinning and dewetting.
• Cryo-EM revealed a novel fibril structure with two jR2R3-P301L copies stabilizing an SLS fold.

Conclusions:

• The identified jR2R3-P301L peptide fibrils can template full-length tau in a prion-like manner.
• This strategy enables the generation of seeding-competent tau fibrils for studying tauopathies.
• Findings provide a foundation for developing novel diagnostic and therapeutic strategies for tauopathies.