A lipid metabolism enzyme is revealed as a new way to raise levels of the key protein in spinal muscular atrophy

Spinal muscular atrophy (SMA) is considered a rare disease. Although it affects one in every 8,000 births, one in every 40 people is a carrier, and it has the highest mortality rate of all hereditary diseases. It mainly affects motor neurons, which are the "wires" that carry messages to the muscles so that they can move. At the molecular level, SMA is caused by a lack of a protein called SMN, which is encoded by two genes: SMN1 (which is missing in most patients) and SMN2 (which produces only 10% of the complete protein). This neurodegenerative disease currently has treatments that are among the most innovative and expensive in the world, but they are not yet able to cure it, especially in adults.

A team led by Antonio Pérez Pulido and Manuel Muñoz, researchers at Pablo de Olavide University, and Rosa Maria Soler, from the University of Lleida and head of the Neuronal Signalling Unit research group at the Lleida Biomedical Research Institute, has identified a biological target for combating spinal muscular atrophy: acid sphingomyelinase (ASM), an enzyme involved in the metabolism of lipids in the nervous system. Blocking its activity increases the amount of SMN, since the lack of this protein causes the disease. The finding connects SMA for the first time with sphingolipids-fats that are essential in cell membranes 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 journal Biomedicine & Pharmacotherapy.

The research team combined the analysis of large amounts of data with experiments on animal models to uncover new clues about spinal muscular atrophy (SMA). First, they explored huge public databases that collect information on what is activated or deactivated under different conditions. This analysis revealed that blocking an enzyme called acid sphingomyelinase could increase levels of the SMN protein, which is key to the proper functioning of motor neurons. They then tested this idea in a simple organism, the Caenorhabditis elegans worm. By switching off the gene equivalent to this enzyme, they observed that SMN levels also increased. Finally, they wanted to see if the same thing happened in a context closer to patients. To do this, they used human motor neurons derived from cells from people with SMA. The results were promising: when the enzyme was blocked, the neurons produced more SMN and showed fewer initial signs of damage. In addition, the team saw that the patients' cells already had high baseline levels of this enzyme and that treating them with the appropriate drugs helped to reduce these levels.

The findings of this research, carried out at the Andalusian Centre for Developmental Biology (CABD, a joint centre of the UPO, the CSIC and the Regional Government of Andalusia) and at the Lleida Biomedical Research Institute (IRBLleida), are highly significant in identifying a new therapeutic use for drugs and because this is the first time that sphingolipid metabolism has been associated with spinal muscular atrophy. This biological process had previously been linked to other neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and Parkinson's.

In addition, the work has made it possible to link SMA to another very similar disease, progressive myoclonic epilepsy, in which the enzyme that performs the opposite step to ASM is mutated, causing a sphingolipid that can become toxic, ceramide, to accumulate in the cell. And it is precisely high levels of ASM that would lead to the same accumulation of ceramide. All this suggests that this sphingolipid, which can be measured in the blood, could be used as a biomarker for the progression of the disease and its current and future treatments.

The research is supported and funded by the GaliciAME and El camino de Elena associations and the Spinal Muscular Atrophy Foundation (FundAME), which have made it possible to take this step forward in understanding the disease and lay the foundations for future advances.

Article: Brokate-Llanos AM, Beltran M, Garzón A, Garcera A, Miralles MP, Celma-Nos F, Campoy-López A, Soler RM, Muñoz 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