Full-length tau seeded by C-shaped tau fibrils is conformationally variable

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Amyloid proteins in neurodegenerative diseases adopt specific structures.
• Prion-like propagation involves soluble monomers adopting fibril seed structures.
• Tau protein's intrinsically disordered regions complicate understanding structural fidelity.

Purpose of the Study:

• Investigate the structural fidelity of cross-seeding full-length tau protein.
• Determine if accelerated fibrillization correlates with faithful seed structure amplification.
• Analyze structural polymorphism and evolution in seeded tau fibrils.

Main Methods:

• Cross-seeding experiments using full-length phospho-mimetic tau (4E tau) and a truncated tau seed.
• Sedimentation gels to assess fibrillization kinetics.
• Solid-state NMR and INEPT NMR to analyze core structure and dynamic disorder.

Main Results:

• Cross-seeded reactions showed accelerated fibrillization kinetics.
• Solid-state NMR revealed structurally variable cores, differing from the seed AD fold.
• Some cross-seeded samples showed polymorphism or resembled unseeded structures.
• INEPT NMR indicated similar dynamic disorder in the fuzzy coat of cross-seeded replicas.

Conclusions:

• Accelerated tau fibrillization kinetics do not necessarily correlate with faithful seed structure amplification.
• Surface-catalyzed nucleation of full-length tau leads to structural polymorphism.
• Full-length tau exhibits structural evolution away from the seed structure.