Elongation of Fibrils Formed by a Tau Fragment is Inhibited by a Transient Dimeric Intermediate

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tau protein aggregation in the brain is linked to tauopathies, a group of neurodegenerative diseases.
• Distinct structural folds of tau aggregates characterize different tauopathies, but the mechanisms of their formation are unclear.
• Understanding tau fibril formation is crucial for developing therapeutic strategies against neurodegenerative diseases.

Purpose of the Study:

• To investigate how mutations in the tau protein fragment tau-K18 affect fibril morphology and formation kinetics.
• To elucidate the mechanism by which distinct tau fibril structures arise and how their elongation is regulated.
• To explore the role of transient tau dimers in modulating fibril elongation.

Main Methods:

• Studied fibril formation using wild-type (wt) tau-K18 and a Lys 280 → Glu mutant (tau-K18 K280E).
• Employed kinetic modeling of seeded aggregation, applying a Michaelis-Menten-like mechanism.
• Investigated the inhibitory effect of tau-K18 K280E fibrils and tau dimers on monomer elongation.

Main Results:

• The tau-K18 K280E mutation resulted in morphologically distinct fibrils (two protofilaments) compared to wt tau-K18 (single protofilament).
• Kinetic modeling showed different catalytic efficiencies for the elongation of wt and mutant tau fibrils.
• Monomeric tau-K18 elongation seeded with tau-K18 K280E fibrils exhibited uncompetitive inhibition at high monomer concentrations, mediated by a transient tau dimer.

Conclusions:

• Mutation-induced changes in tau protein can lead to the formation of distinct fibril structures.
• A transiently formed tau dimer acts as an uncompetitive inhibitor, specifically affecting the elongation of tau-K18 K280E fibrils.
• This quantitative kinetic approach provides insights into the modulation of tau fibril formation and potential therapeutic targets for tauopathies.