Lay summary by Alexander Romero Cabeza, and reviewed by Dr Jon Wood and an MND lay panel
Background
Amyotrophic Lateral Sclerosis (ALS) is a progressive, debilitating condition and the most common type of Motor Neuron Disease (MND). It is characterized by the death of nerve cells called motor neurons, specifically the ‘lower’ motor neurons that connect the spinal cord to the skeletal muscles, controlling movement. A key feature of the disease process is the disruption of these vital connections between nerves and muscles, a process known as denervation. This breakdown happens right at the neuromuscular junction (NMJ), the exact spot where the nerve terminates and the muscle begins, and it is a major factor driving the physical symptoms of ALS.
Scientists now know that motor neuron death is driven by a mix of factors both inside and outside the nerve cells. One major ‘outside’ factor is a disrupted immune response, commonly known as inflammation. This process relies on chemical messengers that spark the defense reaction. These inflammatory substances include chemicals called cytokines and chemokines, which act as alarms that powerfully recruit immune cells to the problem area. ALS is no exception to this; in fact, overactive immune cells have consistently been found in the blood samples of patients with the disease.
For the last two decades, the role of these specific inflammatory products in ALS has remained largely unexplored. However, recent research has highlighted chemokine ligand 2 (CCL2), a chemical distress signal that acts like an emergency flare. It drives the activation of its specific receiver, receptor type 2 (CCR2), which produces dysfunctional defense cells directly into the muscle tissue, leading to denervation. This suggests that the immune system and the neuromuscular junction (NMJ) are deeply intertwined in ALS. Because the breakdown of the NMJ plays such a crucial role in the overall progression of the disease, studying this specific area is helping researchers uncover key pieces of the puzzle that can now be used as new treatment targets.
Why is the study important?
This study is important because, despite strong evidence that an overreactive immune system plays a role in ALS, previous therapies targeting the immune system have not successfully improved patient symptoms. This lack of success could be explained by the fact that the specific molecules driving the most critical damage were not yet known. In this study, researchers used three different genetically modified ALS mouse models and discovered that the CCL2-CCR2 ’emergency flare’ system was a common factor driving immune cells to invade the muscles in all of them. Most importantly, the researchers found that by blocking this specific distress signal directly within the muscle, they could stop the immune cells from invading. By calming this local immune reaction, they successfully halted the damage and protected the vital connection between the nerve and the muscle.
What did the authors do and how did they do it?
Initially, the researchers examined skeletal muscle samples from human ALS patients to confirm the presence of invading immune cells. To accurately study this, they collected muscle samples from the mouse models at various stages of the disease’s progression to see exactly when and how the immune cells began their attack. After identifying the CCL2-CCR2 pathway as the main “distress signal,” they tested a treatment. They injected a neutralizing substance (a protein designed to block the CCL2 signal) directly into the affected muscle.
To ensure their results were accurate, they used a clever technique: they treated the muscle on one side of the mouse and used the same muscle on the opposite side as an untreated internal control. This simplified the experiment and provided a direct comparison between treated and untreated muscles in the same animals.
What are the results?
The experiments confirmed that immune cell invasion into muscle tissue is a consistent hallmark of ALS. The researchers found these immune cells in both muscle tissues from human patients and across all three mouse models, regardless of the subject’s age or how fast the disease was progressing. When looking closer at the most severely affected muscles in mice, the researchers noticed something crucial: the immune cells weren’t just randomly scattered.
They were heavily concentrated right at the neuromuscular junction (the exact spot where the nerve meets the muscle and where the denervation occurs). They also discovered that these immune cells were gathering there early on, before any physical symptoms of muscle weakness even began. By identifying specific “antennas” (CCR2) on these invading cells, the team confirmed that the CCL2-CCR2 pathway discussed earlier was actively driving this attack. Most importantly, when the researchers injected a neutralizing agent directly into the muscle to block the CCL2 distress signal, it prevented immune cells from invading and protected the vital nerve-muscle connection from degeneration.
What do the findings mean going forward for people with the disease?
Overall, this study proves that blocking this specific ‘distress signal’ could be a powerful new way to treat ALS. By calming the local immune reaction, the treatment successfully protected nerve structures and preserved the vital connection at the NMJ. However, there is a limitation to address: in this study, the treatment was injected into just one muscle. Moving forward, future trials will need to explore how to protect muscles throughout the entire body. For example, researchers will need to observe if these therapies can be delivered systemically (such as through the bloodstream) to successfully prevent the breaking of nerve-muscle connections on a much larger scale. Ultimately, if this ‘distress signal’ can be successfully blocked across the whole body, it could become a powerful new strategy to prevent nerve loss and help patients preserve their ability to move for as long as possible, preventing muscle paralysis.
This study can be found at www.nature.com/articles/s41467-025-62351-3#Sec7
Paper title
The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis
Lead author
Bernát Nógrádi, Helena Chaytow and Thomas Gillingwater
Publication details including date of publication
Nat Commun 16, 7053 (2025). https://doi.org/10.1038/s41467-025-62351-3