Spinal muscular atrophy is the most common genetic cause of death in children, affecting about one in 10,000 newborns. As its name suggests, the disease is characterized by the degeneration and loss of motor neurons and, as a consequence, by severe defects in muscle development that in the most severe cases lead to the death of untreated children before the age of two. A study co-led by the Genetic Medicine group of the Vall d'Hebron Research Institute (VHIR) has studied the structure and function of proteins related to spinal muscular atrophy and their interaction with messenger RNA (mRNA), which opens new avenues for the design of new treatments. The results have been published in Protein Science, the journal of the Protein Society, an academic society for the advancement of research on the structure, function, design and applications of proteins.

The genetic cause of SMA has been known for decades: the absence of the SMN1 (Survival of Motor Neuron 1) gene or, less frequently, mutations in this gene. Although there is an almost identical "backup copy" of this gene, SMN2, it does not compensate for the loss of SMN1, because most of the mRNA molecules produced from the SMN2 gene are processed incorrectly in the neurons. This results in the synthesis of a non-functional protein, which is rapidly degraded.

On the other hand, previous studies have found that small increases in the number of correctly processed SMN2 mRNA precursors lead to significant improvements in the quality of life of SMA patients. These observations have stimulated several drug discovery programs, which have been crowned with the recent introduction of the first drugs to treat the disease, nusinersen/Spinraza and risdiplam/Evrysdi. However, many unknowns remain about the molecular basis of mRNA processing and the mechanism of action of these drugs.

In the work presented now, Dr. Eduardo Tizzano, head of the Genetics Medicine Group at VHIR, and Dr. Pablo Fuentes-Prior at the Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau (IIB Sant Pau), present the first three-dimensional (3D) structure of one of the nuclear factors that play a key role in the incorrect processing of SMN2 mRNA, known as Sam68. It has been obtained by X-ray crystallography using synchrotron radiation. The work builds on Dr. Tizzano's previous research on the genetic basis of SMA.

In addition, the researchers have studied how Sam68 and hnRNP A1, another protein essential for aberrant mRNA processing, interact with the SMN2 mRNA molecule. In particular, the research team has been able to demonstrate that the two proteins recognize adjacent motifs in the mRNA encoded by SMN2, form a complex in solution, and identify contact residues between them. Using this information and the previously reported structures of hnRNP A1, they have developed a model of the Sam68-mRNA(SMN2)-hnRNP A1 complex that reproduces all the structural and functional information about the processing mechanism of SMN1/2 mRNA precursors.

The authors emphasize that the results of this investigation of protein structure and function and their interactions with RNA open new avenues for the design of drugs for the treatment of SMA, as well as other diseases in which incorrect mRNA processing plays a prominent role, including cancer.

The work has been made possible thanks to generous grants from the "Daniel Bravo Andreu" Foundation and SMA Europe to Dr. Fuentes-Prior and Dr. Tizzano.