Biomolecular condensates can enhance pathological RNA clustering

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Intracellular aggregation of repeat-expanded RNA is linked to neurological disorders.
• Biomolecular condensates are crucial cellular compartments involved in various biological processes.

Purpose of the Study:

• To investigate the role of biomolecular condensates in irreversible RNA clustering.
• To understand the mechanisms underlying RNA aggregation within these condensates.

Main Methods:

• Studied RNA clustering within multi-component protein-nucleic acid condensates.
• Analyzed the impact of RNA sequence features, secondary structure, and repeat length on clustering.
• Investigated the role of G3BP1 in modulating RNA-RNA interactions within condensates.

Main Results:

• Physiologically relevant and disease-associated repeat RNAs undergo age-dependent percolation transitions to form nanoscale clusters within condensates.
• Homotypic RNA clusters induce multiphasic condensate structures with distinct RNA-rich cores and RNA-depleted shells.
• RNA clustering drives a liquid-to-solid phase transition of biomolecular condensates.
• G3BP1 acts as a heterotypic buffer, impeding intra-condensate RNA clustering independently of ATP.

Conclusions:

• Biomolecular condensates can serve as sites for aberrant RNA aggregation.
• RNA-binding proteins play a critical role in suppressing pathological RNA phase transitions and aggregation.