Liquid-liquid Phase Separation Modulates the Structural Heterogeneity of Tau Amyloid Fibrils.

Area of Science:

• Biochemistry
• Neuroscience
• Biophysics

Background:

• Tau protein exhibits two phase transition types: amyloid aggregation linked to neurodegenerative diseases and liquid-liquid phase separation (LLPS) forming protein condensates.
• The relationship between tau's LLPS and amyloid fibril formation remains incompletely understood.

Purpose of the Study:

• To investigate the interplay between tau's liquid-liquid phase separation and its amyloid fibril aggregation.
• To determine if LLPS influences the structural characteristics and heterogeneity of tau fibrils.

Main Methods:

• Studied tau construct (243-386) phase transitions across varying NaCl concentrations.
• Utilized fluorescence recovery after photobleaching to assess molecular dynamics within condensates.
• Employed Thioflavin T fluorescence and hydrogen-deuterium exchange mass spectrometry to analyze fibril formation and structure.

Main Results:

• Tau (243-386) underwent LLPS below 135 mM NaCl; fibril formation was studied at 100 mM and 150 mM NaCl.
• Molecules within condensates showed reduced dynamics, and amyloid formation occurred throughout condensates, not just at the interface.
• Fibrils emerged from aged condensates, exhibiting distinct structural heterogeneity and local stability differences compared to non-LLPS conditions.

Conclusions:

• LLPS may act as a selective mechanism, favoring the formation of specific structural polymorphs within the heterogeneous population of tau fibrils.
• This finding provides insight into how phase separation influences the structural diversity of amyloid aggregates.