How RNA Clusters Form and Can Be Broken Apart in Brain Disorders

In brain cells affected by Huntington’s disease or ALS, researchers often find RNA molecules clumped together in solid-like clusters. These clusters, which can absorb proteins essential for brain health, are thought to play a role in neurological disorders. However, the process by which these RNA aggregates form has not been fully understood.

A study from the University at Buffalo, published in Nature Chemistry, reveals that small droplets of proteins and nucleic acids within cells, known as biomolecular condensates, contribute to the formation of these RNA clusters. The research team also demonstrated a method to prevent and break apart these clusters using an engineered RNA strand called an antisense oligonucleotide (ASO).

Cells naturally create liquid-like condensates from RNA, DNA, and proteins. These structures can host repeat RNAs—disease-linked RNA molecules with long repeated sequences. Initially, the repeat RNAs are fully mixed within the condensate, but as time passes, they begin to clump together, forming a solid RNA core surrounded by a fluid shell. “Repeat RNAs are inherently sticky, but interestingly, they don’t stick to each other just by themselves because they fold into stable 3D structures. They need the right environment to unfold and clump together, and the condensates provide that,” explained Tharun Selvam Mahendran, the study’s first author.

The researchers found that introducing the RNA-binding protein G3BP1 into the condensate can prevent the repeat RNAs from clustering. To reverse already formed clusters, the team used an ASO, which binds specifically to the repeat RNA and disassembles the aggregates. This disassembly depends on the ASO’s sequence, suggesting the potential for targeted approaches.

Corresponding author Priya Banerjee noted, “What’s exciting about this discovery is that we not only figured out how these clusters form but also found a way to break them apart.”