Blocking Protein Receptor May Prevent Motor Neuron Death, SMA Study Reveals

Blocking a protein receptor called m2R may prevent motor neuron death, leading to new therapies for spinal muscular atrophy (SMA), according to a study.

The research, “Decreased microRNA Levels Lead To Deleterious Increases In Neuronal M2 Muscarinic Receptors In Spinal Muscular Atrophy Models,” was published in the online journal eLife.

SMA is caused by mutations of the SMN gene that impair the proper activity of motor neurons, and therefore muscle and movement control. Only one SMA treatment, Spinraza, has obtained U.S. Food and Drug Administration approval.

Researchers at Brown University wanted to know exactly what causes the disease. The Brown team, led by graduate student Patrick O’Hern, and colleagues at the University of Cologne in Germany discovered a complex cause-and-effect sequence in both worm and mouse models of SMA.

Researchers discovered that loss of the SMN protein disturbs the normal activity of a protein called Gemin3 in C. elegans worms. This, in turn, weakens the work of a MicroRNA that regulates protein production.

One of the roles of that MicroRNA, known as miR-2, is to control the levels of a motor neuron receptor called m2R. These receptors are important because they let neurons know whether they have released enough of the neurotransmitter acetylcholine to prompt a muscle cell to move.

When m2R is working improperly, motor neurons can shut off the release of acetylcholine prematurely, greatly impairing muscle activity.

Researchers also discovered that treating motor neurons with the m2R-blocking drug methoctramine restored the normal activity of these cells, compensating for the lack of SMN and miR-2.

The bottom line is that “if you decrease the activity of these receptors, it could be beneficial,” Anne Hart, study’s senior researcher, said in a news release. “This needs to be tried in other models, too.”

The study suggests that m2R receptors may be a potential target for future SMA therapies. But more studies are necessary to validate the findings in humans, the researchers said.