A modular tool to query and inducibly disrupt biomolecular condensates

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Biology

Background:

• Dynamic membraneless compartments formed by protein condensates are crucial for cellular functions.
• Existing tools allow inducible control over condensate formation but lack options for disassembly.
• Controlling condensate disassembly is essential for understanding their biological roles.

Purpose of the Study:

• To develop a novel tool for inducible control over the disassembly of protein condensates.
• To investigate the utility of this tool in disrupting condensates relevant to neurodegenerative diseases.

Main Methods:

• Developed DisCo (Disassembly of Condensates) utilizing chemical dimerizers to recruit ligands for condensate dissociation.
• Applied DisCo to disrupt FUS condensates, implicated in amyotrophic lateral sclerosis.
• Used DisCo to prevent the formation of polyglutamine-huntingtin condensates, linked to Huntington's disease.
• Combined DisCo with CRY2olig (light-inducible condensate formation) for bidirectional control.

Main Results:

• Successfully demonstrated inducible disruption of protein condensates using DisCo.
• Showcased DisCo's efficacy in targeting disease-associated proteins like FUS and huntingtin.
• Achieved orthogonal, bidirectional control of condensate dynamics (formation and disassembly) using light and rapamycin.

Conclusions:

• DisCo provides a versatile method for inducible control over protein condensate states.
• This tool facilitates deeper understanding of the biological roles of condensates in cellular processes and diseases.
• The ability to manipulate condensate dynamics offers broad utility for biological research and therapeutic development.