Health UK (Commonwealth Union) – Exploring unconventional forms of RNA associated with the development of aggregates in the brains of ALS patients holds promise for innovative treatment avenues.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the deterioration of nerve cells in the spinal cord and brain. Neurodegenerative conditions, such as ALS, dementia, and Alzheimer’s, are major contributors to mortality in the UK, with no established cures.
In addition to observable physical symptoms, a distinctive molecular feature of these diseases is the formation of solid aggregates in the brains of individuals affected. Traditionally attributed to specific proteins, these aggregates have been targeted by various drugs designed to dismantle them, yet none have demonstrated substantial symptomatic improvements.
Now, under the leadership of Dr. Marco Di Antonio at Imperial College London, in collaboration with Dr. Lorenzo Di Michele (University of Cambridge) and Professor Rickie Patani (The Francis Crick Institute and UCL Queen Square Institute of Neurology), the research team has explored an alternative pathway contributing to aggregate formation in ALS. Their discovery highlights the potential involvement of atypical RNA structures in the accumulation of these aggregates.
These findings open the door to the development of novel drugs targeting these RNA formations and suggest the prospect of investigating similar factors in other neurodegenerative disorders. The study, featured in Nature Communications, presents a paradigm shift, with first author Federica Raguseo, who conducted the research during her PhD at the Department of Chemistry at Imperial, emphasizing the possibility that aggregates may be symptomatic rather than causal, challenging the conventional view that protein aggregations are the primary drivers of neurodegenerative diseases for over two decades.
“Looking at the causes of the aggregates may lead us to the causes of the symptoms themselves, which could help us find new ways to tackle these debilitating diseases.”
Imperial researchers recently unveiled a breakthrough in understanding a human protein’s role in fostering the creation of a distinct DNA structure known as multimolecular G-quadruplex (mG4). This unique DNA arrangement comprises four separate strands instead of the conventional two, enabling the connection of distant segments within DNA strands and contributing to DNA condensation within the cell nucleus.
In their latest exploration, the research team shifted their focus to RNA condensation within the C9orf72 gene, particularly in cases of Amyotrophic Lateral Sclerosis (ALS) where this gene undergoes mutations and significant expansion. Within the gene lies a ‘repeat expansion’—a recurring DNA segment transcribed into RNA during the reading process.
Through an investigation into the behavior of C9orf72 RNA, the researchers uncovered that RNA expansions linked to ALS could generate mG4 structures, forming a network that culminates in robust aggregates. Remarkably, these mG4 structures exhibited an ability to aggregate independently of proteins, potentially serving as a foundation for protein aggregation.
To validate this hypothesis, the team demonstrated that the presence of mG4 networks increased the likelihood of protein aggregation. Furthermore, they established that inhibiting mG4 formation not only prevented RNA condensation but also halted the aggregation of proteins.
The next step for the research team involves delving into the correlation between mG4s and protein aggregates within more intricate real-world scenarios. They aim to assess potential influences of the cellular environment and explore viable strategies to impede mG4 aggregation in these complex situations.
The lead researcher Dr Marco Di Antonio, of the Department of Chemistry at Imperial, says “What we have found is not the definitive answer to the puzzle, but we have shown that these unusual RNA structures likely contribute to formation of aggregates in ALS. This offers an alternative pathway for aggregate formation, which should be also looked in other neurodegenerative diseases.
“New therapies are desperately needed for these diseases, and drugs based on disrupting the accumulation of mG4s and other unusual RNA structures could play a key role in the future.”
