Intracellular TDP-43 amyloid nucleates from arrested nascent condensates.

Area of Science:

• Biochemistry
• Cell Biology
• Biophysics

Background:

• TDP-43 protein is central to understanding cellular phase transitions.
• The relationship between physiological condensation and pathological aggregation of TDP-43 remains unclear.
• Intracellular assemblies of TDP-43 exhibit diverse physical properties.

Purpose of the Study:

• To map the phase space of TDP-43 self-assembly in vivo.
• To elucidate the causal relationships between different TDP-43 assembly states.
• To identify conditions governing TDP-43 amyloid formation.

Main Methods:

• Distributed Amphifluoric FRET (DAmFRET) was employed to study TDP-43.
• Complementary biophysical approaches were utilized.
• Experiments were conducted in yeast cells to model in vivo conditions.

Main Results:

• The TDP-43 C-terminal domain (CTD) forms dynamically arrested soluble clusters, not condensates.
• Amyloid formation by CTD clusters requires templating by pre-existing amyloids.
• Full-length TDP-43 features, C-terminal fragments, or stress conditions can block amyloid nucleation by promoting further condensation.

Conclusions:

• TDP-43 amyloid formation is a rare event, contingent on specific physical and biological triggers.
• The findings reveal distinct pathways for TDP-43 self-assembly.
• Understanding these specific conditions may offer novel therapeutic intervention strategies.