New target for Spinal Muscular Atrophy identified

Led by scientists from Brown University and Brown Institute for Brain Science in the United States and the University of Cologne in Germany, a study (Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models, eLife (2017)) now offers new clues to Spinal Muscular Atrophy (SMA), a genetic disease that attacks motor neurons in the brain and spinal cord.

SMA occurs in 1 in 10,000 births, making it the most commonly inherited motor neuron disease in infants and children. Over time, the disease can cause skeletal muscle weakness, atrophy, and premature death in the majority of the patients. More than 95% of patients with SMA have a homozygous deletion or mutation of the SMN1 (Survival Motor Neuron 1) gene, resulting in reduced Survival of Motor Neuron (SMN) protein levels. SMN is found throughout the body, with high levels in the spinal cord. This protein normally plays a role in processing messenger RNA (mRNA), a family of RNA molecules that are crucial for protein synthesis. Moreover, evidence shows that SMN may have additional functions in nerve cells. If we can better understand the consequences of SMN loss, it may lead to new treatment strategies for SMA.

Anne Hart, corresponding author of the paper and a neuroscientist at Brown University, and colleagues as well as researchers from other institutions collaborated to study the pathogenesis of SMA. Using both C. elegans worm and mouse models of SMA, they examined the connection between SMN, Gemin3, and miRNA function. They found that reduced SMN levels hinder the working of Gemin3 and therefore perturb miRNA pathways, including miR-128 suppression of m2R translation. This results in increased m2R expression and neuronal dysfunction in SMA. The m2R protein is a receptor for a key neurotransmitter, called acetylcholine. Overexpression of m2R may be detrimental to motor neurons. When the researchers decreased m2R protein activity, some of the defects seen in the animal models were rescued.

In conclusion, the study indicates that targeting m2R is a potential therapeutic strategy for SMA. Currently, several drugs that block m2R are used in the treatment of certain other diseases. In the future research, the team will test whether these drugs could reduce symptoms in animal models of SMA.

The prevalence of SMA is increasing, which rises awareness about diagnostics and treatment of the frequently fatal disease. The treatment of SMA involves gene replacement surgery or therapy, and patients may receive medications that restore their SMN levels. If confirmed, findings of this study may provide a new treatment options for these patients.

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