RNA Aggregation in Neurodegenerative Disorders: Novel Approaches for Therapeutic Intervention
In a groundbreaking development, researchers are exploring the use of Antisense Oligonucleotides (ASOs) to treat neurodegenerative diseases like Huntington's and ALS. These diseases are characterised by the formation of harmful RNA clusters inside biomolecular condensates, liquid-like droplets composed of RNA, DNA, and proteins [1].
ASOs are short, engineered strands that are complementary to the target RNA. They bind specifically to the RNA aggregates, disrupting the interactions that stabilise these clusters, and causing their dissolution. This prevents the harmful RNA condensates from acting as protein sponges and interfering with normal cell functions [2].
In diseases such as ALS linked to mutations in the FUS gene, pathological RNA condensates form through abnormal RNA methylation and interactions involving retained introns. ASOs targeting the RNA sequences involved can hybridize to these clusters, effectively pulling the RNA aggregates apart and dissolving the condensates [1][2]. This mechanism involves sequence-specific hybridization of the ASO to the target RNA, which disrupts the condensates through steric hindrance and potentially recruits RNase H to degrade the RNA strand in RNA-DNA hybrids [4].
The effectiveness of ASOs depends on their sequence matching the problematic RNAs, allowing precise targeting and minimising side effects [2]. Key mechanistic points include the RNA modifications like N6-methyladenosine (m6A) that stabilise pathogenic aggregates, the ASOs' ability to sterically hinder RNA interactions necessary for condensate integrity, and the potential recruitment of RNase H for enzymatic RNA cleavage [4].
This approach dismantles the liquid-like RNA-protein droplets that, if persistent, contribute to neurodegeneration by sequestering essential RNA-binding proteins and disrupting RNA metabolism [2]. As a result, ASO therapy functions by sequence-specific binding and destabilisation of pathogenic RNA condensates, reversing toxic RNA aggregation in neurodegenerative diseases [1][2][4].
Beyond the immediate therapeutic promise for Huntington's disease and ALS, this research opens new frontiers in biology, synthetic biology, and medicine, recognising RNA's capacity to form both beneficial biological structures and harmful disease-associated aggregates [6]. Basic and clinical research continues to push these molecular approaches closer to real-world treatments [9].
Enhancing or mimicking the activity of natural cellular proteins like G3BP1 could be a strategy to prevent disease-associated RNA clumps [5]. Further development and clinical testing could eventually transform these scientific insights into real-world treatments for neurodegenerative diseases [7].
Patients and families can consider enrolling in trials or explore emerging therapies under expert guidance, while relying on comprehensive care to manage symptoms [8]. Lithium orotate has shown some potential in neuroprotection, but its role in directly addressing RNA clumps in diseases like Huntington's or ALS has not been demonstrated [3].
Dr. Banerjee's ongoing work, supported by a seed grant from the Hypothesis Fund, explores the role of RNA and biomolecular condensates in early life on Earth, hypothesising that condensates helped protect RNA's catalytic functions in harsh prebiotic environments [4]. This research provides a dual perspective, recognising RNA's capacity to form both beneficial biological structures and harmful disease-associated aggregates [10].
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