Study offers new approach for spinal muscular atrophy

April 9, 2013

Spinal muscular atrophy is a debilitating neuromuscular disease that in its most severe form is the leading genetic cause of infant death. By experimenting with an ALS drug in two very different animal models, researchers at Brown University and Boston Children's Hospital have identified a new potential mechanism for developing an SMA treatment.

There is no specific drug to treat (SMA), a family of motor neuron diseases that in its most severe form is the leading of infant death in the United States and affects one in 6,000 people overall. But a new multispecies study involving a drug that treats (ALS) has pinpointed a mechanism of SMA that drug developers might be able to exploit for a new therapy.

The research, published in the Journal of Neuroscience, reports that the drug Riluzole advanced neural cell development in a mammalian model of SMA and restored neuromuscular function and mobility in a worm model of the disease.

Riluzole has already been tested as a therapy in a very small study of severely affected SMA patients. It failed to help. Nevertheless, what makes the new research encouraging, said Anne Hart, professor of neuroscience at Brown and senior author on the paper, is that the study traces the beneficial action of Riluzole to specific "SK2" potassium channels in worm neurons. Humans have these channels too, and if they can be more precisely targeted by a new drug, she said, that could make a more meaningful difference, at least for some patients.

"We're not suggesting based on this that SMA patients should ask their doctors for Riluzole," said Hart, who is affiliated with the Brown Institute for , "but we are suggesting that this pathway would be useful for therapeutic development."

How Riluzole works

Because SMA has a lot in common with ALS, Hart thought Riluzole might still be worth studying in the context of SMA. To do so, she partnered with fellow researchers at Boston Children's Hospital. They worked in mouse neuronal cells while her team at Brown worked in the worms.

For each system, the researchers created SMA models in different ways by disabling the gene that produces the survival motor neuron (SMN) protein. Depletion of that protein causes SMA in people too.

In the mammalian neuronal cells, the Children's Hospital researchers found that Riluzole promoted the growth of axons that was lacking in the SMN-depleted cells. However, Riluzole did this not by increasing SMN levels. Instead, the researchers found evidence that drug treatment matured the neurons more quickly in normal cells.

Most attempts to treat SMA have relied on trying to maintain or restore higher levels of SMN, Hart noted. But Riluzole, or a future drug, may instead be able to work by accelerating cell maturity.

In the worms meanwhile, the Brown researchers found that Riluzole restored two important neuromuscular behaviors of SMA worms: the pumping action that allows the worms to move food through their digestive tracts and the body bending that they perform when swimming.

To learn how Riluzole had this effect, they performed further experiments testing various potassium channels, including SK2, that Riluzole is known to act upon. Losing these channels didn't cause more problems in animals with less SMN protein, but losing the SK2 in particular made neuromuscular function worse. Without the SK2 channels, the Riluzole didn't improve function.

"This told us that Riluzole improves motorneuron function by acting through SK2 channels, which we did not know before," said lead author Maria Dimitriadi, a postdoctoral researcher in Hart's group. "This is important because understanding how SK2 channels affect motorneuron disease may eventually lead to a treatment helping both ALS and SMA patients."

Explore further: New research sheds light on childhood neuromuscular disease

Related Stories

New research sheds light on childhood neuromuscular disease

November 20, 2012

A study by scientists at the Motor Neuron Center at Columbia University Medical Center suggests that spinal muscular atrophy (SMA), a genetic neuromuscular disease in infants and children, results primarily from problems ...

Recommended for you

Rat brain atlas provides MR images for stereotaxic surgery

October 21, 2016

Boris Odintsov, senior research scientist at the Biomedical Imaging Center at the Beckman Institute for Advanced Science and Technology at the University of Illinois in Urbana-Champaign, and Thomas Brozoski, research professor ...

ALS study reveals role of RNA-binding proteins

October 20, 2016

Although only 10 percent of amyotrophic lateral sclerosis (ALS) cases are hereditary, a significant number of them are caused by mutations that affect proteins that bind RNA, a type of genetic material. University of California ...

Imaging technique maps serotonin activity in living brains

October 20, 2016

Serotonin is a neurotransmitter that's partly responsible for feelings of happiness and for mood regulation in humans. This makes it a common target for antidepressants, which block serotonin from being reabsorbed by neurons ...

Overcoming egocentricity increases self-control

October 19, 2016

Neurobiological models of self-control usually focus on brain mechanisms involved in impulse control and emotion regulation. Recent research at the University of Zurich shows that the mechanism for overcoming egocentricity ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.