Lay summary by Dr Amy Keerie, reviewed by Dr Jon Wood and an MND lay panel.
Background
Amyotrophic Lateral Sclerosis (ALS) is the commonest form of Motor Neuron Disease (MND). In this summary MND will be used throughout.
To move muscles in the body, signals are sent from the brain through the spinal cord and then through motor neurons (MNs) which connect with muscles via neuromuscular junctions (NMJs), structures that are similar to synapses, however neuron to muscle rather than neuron to neuron. The signal sent through a MN is similar to an electrical signal which moves as a wave down the axon towards the NMJs. NMJs allow for this signal from the MN to be sent to the appropriate muscle to cause an electrical signal in the muscle, which in turn leads to contraction of the muscle leading to movement (Figure 1). In people living with MND, the MNs stop working and the link to the muscles can get weak as NMJs fail to pass on the signal. One of the proposed mechanisms of MND is hyperexcitability, where there are too many signals so the MN and NMJs are unable to process signals correctly.
Why is the study important?
Hyperexcitability is one way MNs can become damaged and die in MND. Finding potential medicines that help reduce hyperexcitability in MND may lead to new treatments for patients with MND. In this study, they test if a chemical that targets hyperexcitability would be able to lessen symptoms of MND in a kind of mouse which gets symptoms of MND. Some of the techniques used are similar to tests like electromyography (EMG), often used to diagnose MND.
What did the authors do and how did they do it?
The chemical ICA-27243 has been shown to reduce hyperexcitability in MNs. The authors use a kind of mouse which gets symptoms of MND, because the MNs in the mice get damaged. The MND symptoms in these mice happen because MNJs fail to pass on signals to the muscle and the damaged MNs die. Mice like these are treated with ICA-27243 to see if it protects them from damage. In the mice which get symptoms of MND, damage to NMJs and death of MNs leads to a reduction in tests which asses the power and function of muscles such as rotarod or treadmill running test when compared to similar mice which had been given ICA-27243 (Figure 2). Mice which get symptoms of MND were given placebo or ICA-27243 once a day and monitored using these tests.
The authors also look at the amount of signal received by the muscle from the MNs by looking at the electrical activity in hindlimb muscles (Figure 3).
Once the authors had finished studying signals in muscles, they took tissue from the spinal cord to look at the number of MNs that remain and to look at the structure of the NMJs.
What are the results?
All the mice in this part of the summary would soon have shown symptoms of MND. Mice that were given the placebo (no ICA-27243) got weaker quickly in the motor function tests, so they fell off the rotarod and the treadmill much sooner. Mice given the placebo lost weight once the symptoms started, and the electrical signal in the muscles dropped. Mice that were treated with ICA-27243 were shielded from some of the damage so they got weaker more slowly and continued to gain weight. The size of the electrical signals in their muscles dropped more slowly than the mice given placebo.
In the spinal cord tissue, there was less death of MNs in mice that were given ICA-27243 as well as smaller decreases in the number of working NMJs, when compared to mice given the placebo.
What do the findings mean going forward for people with the disease?
The results suggest that ICA-27243 can slow down the decrease in size of electrical signal in muscles and can slow down the drop in motor function test in mice which get symptoms of MND. This suggests that ICA-27243 has the potential to slow down the progression of MND in patients and proves that targeting hyperexcitability may be beneficial in patients, so more researchers can explore this area.
This study can be found at
https://www.sciencedirect.com/science/article/pii/S1878747924000059?via%3Dihub#bib21
Paper title
ICA-27243 improves neuromuscular function and preserves motoneurons in the transgenic SOD1G93A mice
Lead author
Vera M. Masegosa
Publication details including date of publication
Neurotherapeutics, Volume 21, Issue 2, March 2024, e00319