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Unraveling the RNA Puzzle in ALS: A Paradigm Shift in Neurodegenerative Research


4 January 2024

Researchers have identified unusual RNA structures, specifically multimolecular mG4s, as key players in the formation of brain aggregates in ALS. This discovery shifts the focus from protein aggregates to RNA, opening new avenues for treatment strategies in ALS.

In a groundbreaking shift in our understanding of amyotrophic lateral sclerosis (ALS), recent research has brought to light the intriguing role of unusual RNA structures in the disease's progression. The study, published in Nature Communications and stemming from collaborative work between Imperial College London, University of Cambridge, and The Francis Crick Institute, potentially paves the way for new therapeutic strategies against ALS and other neurodegenerative diseases.

The Conventional View and a New Discovery

ALS, a progressive motor neuron disease, has long been associated with the formation of protein aggregates in the brain. Traditionally, research and treatment approaches have concentrated on these protein build-ups, but with limited success in symptom improvement. This has prompted scientists to look beyond the established path, leading to a revolutionary discovery: the involvement of unique RNA structures, specifically multimolecular G-quadruplexes (mG4s), in the formation of these notorious aggregates.

The Role of RNA in ALS

The research, delves into the behavior of the C9orf72 gene, known to be mutated in some ALS cases. This gene contains a hexanucleotide repeat expansion that, when transcribed into RNA, forms mG4s. These structures, comprising four strands of RNA, have now been shown to lead to solid aggregates, independent of proteins. This contradicts the long-held belief that protein aggregates are the primary culprits in ALS.

First author Federica Raguseo, who undertook the research for her PhD in the Department of Chemistry at Imperial, said: “For more than 20 years we have looked at protein aggregations as the cause of neurodegenerative diseases, but the poor performance of many candidate drugs suggests we might be missing something: that aggregates may be a symptom, rather than a cause. 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.”

Implications and Future Directions

The findings from these tests, both in laboratory settings and in spinal motor neurons of ALS patients, suggest that targeting these unusual RNA structures could offer a new therapeutic approach. Dr. Marco Di Antonio, leading the research at Imperial College London, emphasized the potential of drugs disrupting the accumulation of mG4s, not only in ALS but possibly in other neurodegenerative diseases as well.

For decades, the focus on protein aggregates may have overshadowed critical aspects of neurodegenerative diseases. The revelation that RNA structures like mG4s can form protein-free condensates opens a new frontier in our fight against ALS and related conditions.

A New Paradigm in Neurodegenerative Disease

The implications of this study extend beyond ALS, offering a fresh perspective on neurodegenerative diseases as a whole. It underscores the complexity of these conditions and the need for a multifaceted approach in both research and treatment.

Abstract of the research

The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques...


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