Neurodegenerative disorders like Huntington’s disease and Amyotrophic Lateral Sclerosis (ALS) have long been linked to the presence of stubborn clumps of RNA inside brain cells. These solid-like RNA clusters act like sponges, soaking up proteins critical for maintaining healthy brain function, thereby contributing to neurological decline. Despite their significance, the biological mystery of how these harmful RNA aggregates form—and how to dismantle them—has eluded researchers for years.
Recent breakthroughs from University at Buffalo scientists, published in Nature Chemistry, have shed light on this enigma by uncovering the role of tiny protein and nucleic acid droplets inside cells that foster the formation of these RNA clusters. Crucially, the researchers have also demonstrated a promising way to prevent and even reverse these clusters, potentially paving the way for novel treatments for neurodegenerative diseases.
How RNA Clusters Form in Cells
Inside cells, biomolecular condensates—liquid-like droplets formed from RNA, DNA, and proteins—play important roles in organizing cellular contents and facilitating biochemical reactions. These condensates are dynamic and can change properties over time.
The study explains that disease-linked “repeat RNAs,” which contain abnormally long repetitive sequences, tend to accumulate inside these condensates. Initially, these repeat RNAs are evenly mixed inside the droplets, but as the condensates age, the RNA molecules begin to clump together, forming a dense, solid-like RNA-rich core surrounded by an RNA-depleted fluid shell.
“Repeat RNAs are inherently sticky, but they don’t simply stick to each other on their own because they fold into stable 3D structures,” explains Tharun Selvam Mahendran, the lead PhD student in the research team. “However, the unique environment inside these condensates causes the RNA molecules to unfold and clump, which leads to the solid clusters.”
Importantly, the clusters persist even after the original condensate dissolves, which partly explains why they have been considered irreversible.
Preventing RNA Cluster Formation
The researchers discovered that a natural cellular protein called G3BP1 can prevent these harmful RNA clusters from forming. G3BP1 is an RNA-binding protein that interferes with the RNA-RNA sticking interactions.
“It’s like adding a molecular ‘blocker’ into a solution where crystals are growing,” says Dr. Priya Banerjee, the study’s corresponding author. “G3BP1 binds to the sticky RNAs and prevents them from interacting with each other, thus stopping clusters from forming in the first place.”
This insight reveals how cells may naturally regulate RNA aggregation and suggests that enhancing or mimicking the activity of G3BP1 could be a strategy to prevent disease-associated RNA clumps.
Comparison to Lithium Orotate and Reduction of Neuroinflammation
Lithium orotate has shown some potential in neuroprotection, particularly in Alzheimer’s disease models, but its role in directly addressing RNA clumps in diseases like Huntington’s or ALS has not been demonstrated and remains speculative. Studies in mice indicate that lithium orotate, a form of lithium salt, can restore lithium levels in the brain, reduce pathological features such as amyloid-β plaques and tau phosphorylation, and improve memory without notable toxicity at low doses. These effects are thought to involve lithium’s general neuroprotective mechanisms, including inhibition of the enzyme GSK3β, reduction of neuroinflammation, and promotion of cellular resilience, rather than a targeted action on RNA aggregates.
Disassembling Existing RNA Clusters with Antisense Oligonucleotides
While prevention is critical, many patients already harbor persistent RNA clusters by the time symptoms appear. Addressing this, the team employed a powerful tool: antisense oligonucleotides (ASOs). ASOs are short, engineered strands of RNA designed to bind specifically to complementary RNA sequences.
When introduced to RNA clusters, these ASOs can latch onto the problematic repeat RNAs and pull them apart, breaking down the solid aggregates into dispersed molecules. The ability of the ASO to dissolve clusters depends heavily on its sequence; only the precise complementary sequence is effective, highlighting the potential for highly targeted therapeutic design.
“This method points to exciting prospects for using ASOs to selectively dismantle toxic RNA clusters that contribute to neurodegeneration,” says Banerjee. “It’s a big step forward because it shows not only how these clusters form, but also how we might safely break them apart.”
Broader Implications and Future Directions
Beyond the immediate therapeutic promise for Huntington’s disease and ALS, this research enhances our understanding of RNA’s behavior within cells and the fundamental physics of biomolecular condensates. Dr. Banerjee’s ongoing work, supported by a seed grant from the Hypothesis Fund, even explores the role of RNA and condensates in early life on Earth, hypothesizing that condensates helped protect RNA’s catalytic functions in harsh prebiotic environments.
This dual perspective—recognizing RNA’s capacity to form both beneficial biological structures and harmful disease-associated aggregates—opens new frontiers in biology, synthetic biology, and medicine.
Summary: How to Get Rid of RNA Clumps
1. Leveraging Natural RNA-Binding Proteins: Enhancing or mimicking proteins like G3BP1 that prevent harmful RNA aggregation can stop clusters before they form.
2. Using Antisense Oligonucleotides (ASOs): These small, custom-designed RNA fragments specifically bind and disassemble existing RNA clusters, offering a potential therapeutic approach.
3. Targeted Design Based on RNA Sequence: The effectiveness of ASOs depends on their sequence matching the problematic RNAs, allowing precise targeting and minimizing side effects.
This groundbreaking research provides a clearer picture of RNA cluster formation and introduces practical strategies—both preventive and corrective—to address one of the key molecular hallmarks of devastating neurodegenerative diseases. Further development and clinical testing could eventually transform these scientific insights into real-world treatments.
To get real, however, no approved or easily accessible treatment currently exists to directly dissolve RNA clumps in these diseases outside of experimental ASO therapies in clinical trials. Patients and families can consider enrolling in trials or explore emerging therapies under expert guidance, while relying on comprehensive care to manage symptoms. Meanwhile, basic and clinical research continues to push these molecular approaches closer to real-world treatments.