Precision proteoform design for 4R tau isoform selective templated aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Prion-like spread of tau conformers is characteristic of tauopathies.
• Tauopathies involve the aggregation of tau protein, a key component of microtubules.

Purpose of the Study:

• To investigate the structural basis of tau fibril seeding and propagation.
• To explore the differential seeding activity between 4R and 3R tau isoforms.
• To identify potential therapeutic targets for tauopathies.

Main Methods:

• A 19-residue tau peptide probe with a P301L mutation was synthesized.
• Fibril formation and seeding assays were performed.
• Fully atomistic replica exchange molecular dynamics (MD) simulations were employed.
• Conformational analysis and isoform-specific mutation studies were conducted.

Main Results:

• The tau peptide formed seeding-competent fibrils with a high β-sheet content and a U-shaped fold specific to 4R tauopathy.
• These fibrils induced aggregation of 4R tau but not 3R tau.
• MD simulations identified an aggregation-competent U-fold and an aggregation-prohibiting β-hairpin structure.
• Specific amino acid substitutions modulated the seeding activity, demonstrating isoform specificity.

Conclusions:

• Tau peptide fibrils act as templates for 4R tau propagation, functioning as partial prions.
• The unique U-fold in 4R tau fibrils is critical for seeding and propagation.
• Findings suggest opportunities for tau isoform-specific therapeutic interventions in tauopathies.