R-Roscovitine, a small molecule that promotes calcium entry in nerve cells, restored neuron-muscle communication, reduced the loss of motor neurons, and prolonged the survival of mice with spinal muscular atrophy (SMA), a study reports.

The researchers said this molecule could be used to support other SMA therapies, such as Spinraza and Zolgensma, that take longer to produce the desired effects in the body.

The study, “ R-Roscovitine Improves Motoneuron Function in Mouse Models for Spinal Muscular Atrophy, ” was published in the journal iScience.

Loss of motor neurons — specialized nerve cells that control voluntary muscle movements — and problems in the communication between neurons and muscles are both hallmarks of SMA.

The genetic neurodegenerative disease is normally caused by mutations in the SMN1 gene that compromise the production of the SMN protein. Although that has been known for many years, it is still unclear how the lack of the SMN protein impairs motor neuron function.

Research in mice models of SMA revealed that motor neurons affected by the disease had a reduced number of the voltage-gated calcium channels that are crucial for the transmission of nerve signals. Those calcium channels are specialized passageways found in the membrane of excitable cells — ones that can be stimulated to create a tiny electric current — including muscle cells and neurons, that allow calcium ions (Ca2+) to flow into cells.

A similar deficiency in calcium channels also has been reported at the neuromuscular junction, which is the site where motor neuron terminals communicate with muscle cells and release signals to trigger muscle contraction.

Altogether, these findings suggest that problems in calcium ion transport in neurons may be at the basis of motor neuron malfunction and loss in people with SMA.

Now, researchers at University Hospital Würzburg, in Germany, in collaboration with colleagues at University of Seville, in Spain, sought to test whether restoring the normal flow of calcium would be sufficient to compensate for the motor neuron defects associated with SMA.

The team treated different mice models of SMA with a small molecule called R-Roscovitine. This molecule delays the inactivation of calcium channels, keeping them open for longer periods of time and increasing the influx (entry) of calcium ions into neurons.

The results showed that treatment with R-Roscovitine prolonged the survival of sick mice and reduced the loss of motor neurons in the animals’ spinal cords.

It also stimulated the communication between motor neurons in the spinal cord at special junctions called synapses. According to the researchers, the molecule was even able to “wake up” synapses that were dormant.

R-Roscovitine also restored communication between neurons and muscles at the neuromuscular junction, increasing the number of active motor nerve endings, and stimulating the release of neurotransmitters — chemical substances that allow nerve cells to communicate.

The treatment also was found to increase calcium signaling and to promote the differentiation of mice motor neurons cultured in a lab dish.

Based on these findings, the team concluded that these effects were primarily mediated by R-Roscovitine’s ability to promote calcium influx into motor neurons. The investigators say other mechanisms also may be involved. To understand if that is the case, additional research will be needed.

“Everything considered, R-Roscovitine might support the current SMA therapies with antisense oligonucleotides Spinraza ] or SMN gene transfer via an adeno-associated virus [ Zolgensma ],” the researchers said.

That means that, for patients being treated with Spinraza or Zolgensma, R-Roscovitine may be useful at an early phase, while those medications are still not in effect, the team said.

In addition to SMA, R-Roscovitine also could be useful for other motor neuron diseases associated with defects in calcium transport, they said.