Nanoscale domains govern local diffusion and aging within FUS condensates

Area of Science:

• Cellular Biology
• Biophysics
• Neuroscience

Background:

• Biomolecular condensates are crucial for cellular processes, regulating RNA and protein activity.
• Understanding local regulation within condensates and early disease transitions is challenging.
• Neurodegenerative diseases like ALS involve problematic condensate phase transitions.

Purpose of the Study:

• To investigate the spatial organization and dynamics of molecules within liquid-like condensates.
• To explore the role of condensate structure in disease-related phase transitions, specifically Fused in Sarcoma (FUS) aggregation in ALS.
• To develop a method for tracking molecules within condensates at the single-molecule level.

Main Methods:

• Developed a surface multi-tethering technique for intra-condensate single-molecule tracking.
• Utilized fluorescently labeled RNA and protein molecules.
• Modeled condensates using the RNA-binding protein Fused in Sarcoma (FUS).

Main Results:

• Identified distinct nanometer-scale domains (nanodomains) within condensates where RNA and protein diffusion is confined.
• Observed that nanodomains possess unique connectivity and chemical environments.
• Found that nanodomain repositioning during condensate aging promotes FUS fibrilization at the condensate surface, a process accelerated by ALS drugs.

Conclusions:

• Nanodomain formation is a key mechanism governing condensate function, impacting biomolecule sequestration and percolation.
• Condensate nanostructure plays a critical role in aging and transitions to solid-like states relevant to neurodegenerative diseases.
• The study provides insights into early disease intermediates and potential therapeutic targets for ALS.