Spinal Muscular Atrophy (SMA) is considered a rare disease. Although it affects one in eight thousand births, one in forty people is a carrier and has the highest mortality rate of all hereditary diseases. It mainly affects motor neurons, which are the 'cables' that carry the message to the muscles to move. At the molecular level, AME is produced due to the lack of a protein called SMN, encoded by two genes: SMN1 (which is missing in most patients) and SMN2 (which produces only 10% complete protein); this neurodegenerative disease currently has treatments that are among the most innovative and expensive in the world, but still fail to cure it, especially in the case of adults.

A team led by Antonio Pérez Pulido and Manuel Mu'oz, researchers from the Pablo de Olavide University, i Rosa Maria Soler, from the University of Lleida and responsible for the Neuronal Signaling Unit  from the Lleida Biomedical Research Institute, has identified a biological target to combat Spinal Muscular Atrophy: Acid Sphingomielinase (ASM), an enzyme involved in the metabolism of the lipids of the nervous system. By blocking its activity, the amount of MNS increases, since the lack of this protein causes the disease. The finding connects for the first time the AME with the sphingolipids -essential grains in the membrane of the cells and for the coordination of 'messages', especially in the nervous system- and opens the door to new therapeutic strategies based on existing drugs. The work has been published in the scientific journalBiomedicine & Pharmacotherapy.

The research team combined the analysis of large amounts of data with experiments in animal models to discover new clues about spinal muscular atrophy (SMA). First, they explored huge public databases that collect information about which genes are activated or turned off under different conditions. This analysis revealed that blocking an enzyme called acid sphingomyelinase could increase the levels of the SMN protein, key to the proper functioning of motor neurons. Then, they tested this idea in a simple organism, the worm & nbsp;Caenorhabditis elegans. By turning off the gene equivalent to this enzyme, they observed that levels of SMN also increased. Finally, they wanted to check if the same thing happened in a context closer to patients. For this reason, they used human motoneurons derived from cells of people with AME. The results were promising: by blocking the enzyme, the neurons produced more MNS and showed fewer initial signs of damage. In addition, the team found that patients' cells already had high levels of this enzyme as their basis, and that treating them with the right drugs helped to reduce them. The findings of this research, carried out at the Andalusian Center for Developmental Biology (CABD, a joint centre of the UPO, the CSIC and the Junta de Andalucía) and at the Biomedical Research Institute of Lleida (IRBLleida), are of great relevance, to identify a new therapeutic use of drugs and because it is the first time that the metabolism of sphingolipids is associated with spinal mucular atrophy. This biological process had already been related to other neuronal diseases such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer's or Parkinson's. In addition, the study has allowed the association of AME with another very similar disease, Progressive Myoclonus Epilepsy, in which the enzyme that takes the opposite step to ASM is mutated and causes a sphingolipid that can become toxic, ceramide, to accumulate in the cell. And, precisely, high levels of ASM would lead to the same accumulation of ceramide. All this suggests to this sphingolipid, which can be measured in blood, as a biomarker of the progression of the disease and its present and future treatments.

The research is supported and funded by the associations;GaliciAME i El camino de Elena i de la Fundación Atrofia Muscular Espinal (FundAME) that have made it possible to take this step in the knowledge of the disease and lay the foundations for future advances.

Source:IRBLleida0 1
Article: Brokate-Llanos AM, Beltran M, Garzón A, Garcera A, Miralles MP, Celma-Nos F, Campoy-López A, Soler RM, Mu.oz MJ, Pérez-Pulido AJ. (2025). Inhibition of acid sphingomyelinase increases SMN levels and connects sphingolipid metabolism to Spinal Muscular Atrophy. Biomedicine & Pharmacotherapy; 192:118610. https://doi.org/10.1016/j.biopha.2025.118610