Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by the progressive loss of motor neurons, the cells that control voluntary muscle movements. To date, there is no effective cure for this rare disease.

In a recent study coordinated by Sapienza University of Rome and the Italian Institute of Technology (IIT) in Rome, published in the journal Nature Communications and funded by an ERC-Synergy project, it was discovered that a drug already used in experimental cancer therapies could also have beneficial effects on ALS, opening up important new therapeutic prospects.

The researchers, coordinated by Irene Bozzoni of the Charles Darwin Department of Biology and Biotechnology of Sapienza University of Rome and the CLNS2 centre at IIT in Rome, started by studying specific conditions that cause structures called stress granules to form in cells. The function of these structures is to temporarily protect RNA and protein molecules until the stress state is resolved. Approximately 10% of all ALS cases are caused by mutations in proteins that, in many cases, are components of stress granules. These alterations result in the production of aberrant proteins that turn the granules into toxic aggregates for motor neurons. In particular, in ALS, as in other neurodegenerative diseases, what is altered are the number, composition, and formation and dissociation dynamics of these granules.

The team of researchers discovered that a specific chemical modification of RNA, known as N6-methyladenosine (m6A), plays a crucial role in altering the dynamics of granule formation and dissociation in particularly aggressive forms of ALS: the disease is characterised by increased m6A levels and their restoration to physiological levels can re-establish the normal properties of stress granules.

"We succeeded in decreasing m6A levels using a molecule (STM2457) currently used in clinical trials for the treatment of leukaemic tumours", says Irene Bozzoni. This discovery opens up the possibility of also using it as a new therapeutic approach for the treatment of ALS.

The results of the study represent a valuable contribution to the understanding of the cellular mechanisms underlying the disease and, above all, identify RNA modifications as promising therapeutic targets to combat ALS.

References:

M6A reduction relieves FUS-associated ALS granules - Di Timoteo et al.

Nature Communications – DOI: 10.1038/s41467-024-49416-5

Further Information

Irene Bozzoni

Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome

irene.bozzoni@uniroma1.it