Computer model shows why the timing of ALS treatment is critical
Targeting specific spinal cells protects motor neurons in late-stage disease: Study
- ALS involves motor neuron death and disrupted neural networks.
- Loss of V1 interneurons impairs muscle control by unbalancing signals.
- Stabilizing V1 interneurons can protect motor neurons, but treatment timing is critical.
Scientists have developed a new computer-based model that mimics the spinal cord’s neural networks to predict how nerve cells degenerate in amyotrophic lateral sclerosis (ALS).
Using this simulation, researchers discovered that targeting a specific group of “coordinator” cells, known as V1 interneurons, could prevent motor neuron death. However, findings indicate that stabilizing these cells can preserve motor function, but treatment may be effective and safe only during the later stages of the disease.
The study, “Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study,” was published in Neurobiology of Disease.
The role of interneurons in muscle control
ALS is marked by the death and degeneration of motor neurons, the nerve cells that control movement. The loss of these cells ultimately drives ALS symptoms, but the exact biological mechanisms that lead to motor neuron problems in ALS are not fully understood.
In most people with ALS, motor neurons in the spinal cord are the first to start showing problems. Within the spinal cord, motor neurons are enmeshed with other nerve cells, including interneurons, or specialized nerve cells that form connections between different parts of the nervous system, helping to coordinate complex neurological activity.
Normally, when a person moves, certain muscles need to contract while others relax. For example, when someone raises their arm, the tricep contracts while the bicep relaxes. While motor neurons control actual muscle movement, interneurons help coordinate their activity so that all movements occur in sync.
Previous work done in a mouse model suggested that, in ALS, motor neurons may not actually be the first nerve cells to show problems. Instead, the mouse study suggested that the first spinal nerve cells to show problems are a specific population of interneurons, called V1 interneurons.
Building on that study, researchers have now developed a detailed computer model to simulate how motor neurons and interneurons in the spinal cord normally act to coordinate movement. Then, they tested the effects of removing the V1 interneurons, mimicking what was seen in the ALS mice.
“During ALS, it is known that neurons die and that the communication between [nerve] populations break down,” Beck Strohmer, PhD, study co-author and postdoctoral researcher at the University of Copenhagen, said in a university news story. “We model this by removing neurons from affected populations and by reducing the number of connections from affected populations. This allows us to model disease progression. In a similar way, we can model and test treatment strategies by saving neurons or strengthening communication.”
The researchers found that, without V1 interneurons, the balance between contracting and relaxing signals gets disrupted, leading to too many signals telling muscles to contract and not enough telling them to relax. This dysregulation in neurological circuitry may ultimately contribute to motor neuron stress and damage in ALS, the researchers said.
In further tests using their model, the researchers found that stabilizing V1 synapses (connections with other nerve cells) could help restore these nerve circuits and prevent the death of motor neurons and of other interneurons called V2a. Tests using a genetically engineered mouse model yielded results consistent with the computer-based models.
“Hypotheses generated by models need to be tested on animal models because it is impossible to model all the complexities of a biological system,” said Ilary Alodi, PhD, co-author of the study at the University of St. Andrews. “In this study, we predicted that the applied treatment strategy in the model would save a specific population of neurons. We then looked at this neuron population in the treated mice and found that hypothesis held true.”
Finding the right therapeutic window
The researchers then ran further tests using their computer model to evaluate when a treatment to stabilize V1 synapses would be most effective. They found that such treatment could improve nerve signaling needed for movement, even after motor neurons began to die.
However, if treatment was started too early, when nerve circuitry was still adjusting to the loss of V1 signaling, this same type of stabilization would instead lead to the opposite problem: too many signals telling muscles to relax and not enough telling them to contract.
These findings emphasize the importance of careful timing when designing potential ALS treatments, the researchers said.
“We predict that synaptic stabilization of V1 interneurons can reduce flexor-biased activity and preserve [motor neuron] output, but only after synaptic dynamics have recovered. These findings highlight the importance of intervention timing,” the team concluded.
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