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How the Loss of a Single Protein Leads to a Relentless Neuromuscular Disease

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A new study has laid out the steps that connect the neuromuscular disorder spinal muscular atrophy (SMA) to the mutations in the gene SMN1 that cause the condition. The research suggests that the survival motor neuron 1 (SMN1) protein that is normally produced from SMN1 is a regulator of a cellular process called translation, which may explain how the mutations affect motor neurons and points the way to a better understanding of SMA.

The study was published in Nature Cell Biology by a Europe-wide effort that included researchers from the University of Edinburgh, Utrecht University and the University of Trento, coordinated by the Institute of Biophysics in Italy.

SMA is a progressive neuromuscular disease that affects motor neurons, the nerve cells that carry signals to and from our muscles. It leads to muscle weakness that gradually worsens over time. The disease has four different presentations, with the most severe type presenting in babies less than six months old. It affects roughly 1 in every 10,000 newborns. SMA is an inherited genetic condition, and researchers have long known that mutations in SMN1 are the cause of the disease. What has been less clear is why those mutations, which stop the gene producing its protein product SMN1, lead to SMA.

The European team identified that the SMN1 protein regulates other proteins called ribosomes. These are essential for a cellular process called translation. In translation, ribosomes take the mRNA code obtained from DNA instructions and turn them into proteins that can then get on with their roles in the cell.

The study suggests that ribosomes regulated by SMN1 usually help make proteins that control processes in motor neurons such as neurogenesis (the maturation of nerve cells), ubiquitination (a process that involves marking up proteins for destruction) and lipid metabolism. Without SMN1, these proteins are not produced properly, resulting in motor neurons having reduced function and stability, leading to SMA symptoms.

SMN1 has several other important roles in the cell, such as in the synthesis of important cellular molecules called ribonucleoparticles. This study represents the first time SMN1’s function in translation has been investigated in the context of SMA pathology.

Senior author Tom Gillingwater, a professor of anatomy at the University of Edinburgh, said, “This collaborative project highlights new avenues for targeting these pathways when they go wrong, as they do in disorders such as SMA. It has also revealed fundamental insights into how our bodies control the generation of new proteins in the nervous system.”


Lauria F, Bernabò P, Tebaldi T, et al. SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy. Nature Cell Biology. Published online September 21, 2020:1-13. doi:10.1038/s41556-020-00577-7