The cell next door: could support cells help damage spread in motor neurone disease?

New laboratory research into amyotrophic lateral sclerosis (ALS) suggests that, in one genetic form of the disease, an abnormal protein may disrupt the cells responsible for supporting motor neurones.

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ALS is the most common form of motor neurone disease, or MND (Kiernan et al., 2011). Motor neurones neither live nor die in isolation. Each one is surrounded by cells that supply fuel, clear waste and help to keep its chemical environment stable (Sofroniew and Vinters, 2010). That cellular neighbourhood is the starting point for an intriguing piece of new research. In experiments using cells grown in laboratory dishes and genetically modified mice, scientists followed an abnormal protein as it entered support cells called astrocytes. Once inside, it activated an internal signalling process associated with increased production of hydrogen peroxide, a reactive chemical that cells produce naturally but which can become harmful in excess (Wu et al., 2025; Sies and Jones, 2020).

The most important limitation belongs near the beginning, not buried at the end. The researchers did not show the complete sequence, from the abnormal protein entering an astrocyte to the cell producing more hydrogen peroxide, in astrocytes derived from people with ALS, in human brain or spinal-cord tissue, or in people taking part in a clinical study (Wu et al., 2025). For now, it is a laboratory mechanism with possible human relevance, rather than a confirmed mechanism of human ALS.

The intriguing part is not simply the detection of hydrogen peroxide. Researchers have investigated harmful reactive chemistry in experimental ALS models for years (Rojas et al., 2015). What is new is the attempt to place astrocytes inside a specific chain of events that begins with an abnormal protein and ends with a potentially more hostile environment around the neurone (Wu et al., 2025).

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The neurone and its maintenance crew

Motor neurones carry instructions from the brain and spinal cord to the muscles, allowing people to move, speak, swallow and breathe (Kiernan et al., 2011). In ALS, these neurones progressively deteriorate and die. As their connections to muscles are lost, movement becomes increasingly difficult (Kiernan et al., 2011).

There is no single biological explanation for every case. Genetic and cellular influences can contribute in different combinations, and researchers have also investigated possible environmental influences (Kiernan et al., 2011). This diversity is one reason broad claims about “the cause of ALS” should be treated cautiously.

For years, much of the research concentrated on faults inside motor neurones. That was understandable, but a neurone is not a self-sufficient electrical cable. Its survival depends heavily on neighbouring cells, including astrocytes (Sofroniew and Vinters, 2010). Astrocytes take their name from their star-like shape. They assist with energy supply, influence inflammation and remove excess chemical messages, called neurotransmitters, from the spaces between nerve cells (Sofroniew and Vinters, 2010). They also contribute to the blood–brain barrier, the protective boundary that controls the movement of substances between the bloodstream and nervous tissue (Sofroniew and Vinters, 2010).

A useful way to picture astrocytes is as a specialised maintenance crew. They keep the neighbourhood supplied, clean and chemically stable while neurones carry out their demanding work. If the crew stops delivering supplies or clearing harmful substances, the neurone may struggle. If those same cells begin releasing damaging chemicals, the relationship becomes more dangerous.

This possibility has experimental history behind it. In 2007, two independent groups studied mutations in another gene associated with inherited ALS, called superoxide dismutase 1 (SOD1). They found that astrocytes carrying mutant SOD1 could damage otherwise healthy motor neurones in laboratory cultures (Nagai et al., 2007; Di Giorgio et al., 2007). The motor neurones did not need to carry the mutation themselves for the harmful effect to appear (Nagai et al., 2007; Di Giorgio et al., 2007). Scientists call this non-cell-autonomous toxicity. The name is formidable; the idea is not. A cell may be harmed by faults developing in its neighbours as well as by faults of its own.

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A genetic instruction stuck on repeat

The newer research enters the story through a gene called C9orf72. An unusual expansion within this gene is one of the most common known genetic causes of ALS and frontotemporal dementia, particularly in populations of European ancestry (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Frontotemporal dementia is a brain disorder that can produce changes in behaviour, personality and language (Balendra and Isaacs, 2018). The expansion can be associated with ALS, frontotemporal dementia or features of both conditions (Balendra and Isaacs, 2018). Most people with ALS do not carry it, although it accounts for a substantial proportion of inherited cases (Balendra and Isaacs, 2018).

Inside C9orf72 is a short deoxyribonucleic acid (DNA) sequence represented by the letters GGGGCC. People without the disease-associated expansion usually carry relatively few copies, whereas affected carriers may have hundreds or thousands of repeats (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Imagine a line in an instruction manual being copied repeatedly until it begins to interfere with the rest of the page. That gives a rough sense of the problem, although the biology is more complicated than a printing error.

Researchers are investigating at least three overlapping consequences. The expansion may reduce the availability of the normal C9orf72 protein; the unusually long copy of genetic information produced from the DNA may itself cause disruption; and the repeat may lead to the production of abnormal proteins (Balendra and Isaacs, 2018). These routes may operate together rather than competing as separate explanations (Balendra and Isaacs, 2018). The temporary copy of genetic information made from DNA is called messenger RNA, or mRNA. In C9orf72-associated disease, the expanded repeat RNA may interfere with normal cellular processes (Balendra and Isaacs, 2018).

The repeat can also produce abnormal proteins built from pairs of amino acids, the small chemical building blocks from which proteins are made. Because the same pair occurs repeatedly, scientists call them dipeptide-repeat proteins (Balendra and Isaacs, 2018). The new study concentrates on one of these proteins, called poly-PR. Its name describes its composition: P is the scientific one-letter abbreviation for proline, R represents arginine and poly indicates that the pair appears many times. The protein can therefore be pictured as a sequence reading PR–PR–PR–PR–PR (Balendra and Isaacs, 2018).

Another repeat protein, poly-GR, consists of repeating pairs of glycine and arginine. Poly-PR and poly-GR both contain large amounts of arginine and have shown pronounced toxicity in experimental systems, although their relative contribution to human ALS remains unresolved (Balendra and Isaacs, 2018). Poly-PR is one possible contributor to C9orf72-associated ALS. Treating it as the sole explanation would give the science a certainty it has not earned.

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Following the molecular trail

The researchers detected poly-PR outside cells engineered to produce it. They then found that previously unexposed astrocytes could take up the protein from their surroundings. How it enters an astrocyte remains uncertain; the study demonstrated uptake under its experimental conditions but did not establish the full entry mechanism (Wu et al., 2025).

Once inside the cultured astrocytes, poly-PR activated part of an internal alarm system used by cells responding to infection, injury and stress. This signalling system is called nuclear factor kappa B (NF-κB). Prolonged NF-κB activation can contribute to harmful inflammatory responses (Wu et al., 2025).

The researchers then followed one messenger within that system. This protein, called p65, moved into the astrocyte’s nucleus, the compartment containing DNA and controlling which genetic instructions are used. Think of p65 as an alarm message entering a control room. Once inside, it can alter the instructions being followed. One of the affected instructions was a gene called NADPH oxidase 4 (NOX4). The gene carries the information needed to produce an enzyme associated with the generation of reactive oxygen chemicals. After exposing astrocytes to poly-PR, the researchers detected more temporary copies of the NOX4 instruction and more NOX4 protein (Wu et al., 2025).

In technical language, the cells showed increased NOX4 expression. That wording is important. The experiments showed that the cells produced more NOX4 messenger RNA and protein; they did not directly measure every aspect of the enzyme’s activity.

Alongside the increase in NOX4 expression, the researchers detected more hydrogen peroxide inside and outside the astrocytes. Experiments designed to interrupt parts of the sequence supported a connection between poly-PR, p65, NOX4 expression and hydrogen-peroxide production (Wu et al., 2025). Stripped of the technical names, the proposal is easy to follow. An abnormal protein enters an astrocyte, activates an internal alarm and changes what the cell releases into its surroundings.

Hydrogen peroxide needs careful handling in this account. It belongs to a group of reactive oxygen chemicals known as reactive oxygen species, but hydrogen peroxide is not itself a free radical. Cells use controlled amounts of it for ordinary biological signalling (Sies and Jones, 2020). A working cell produces reactive chemicals in much the same way that a running engine produces heat. Some heat is expected, and the machinery can manage it. Trouble begins when production exceeds the capacity of the systems keeping it under control.

An unhealthy imbalance between reactive chemicals and the systems regulating them is called oxidative stress (Sies and Jones, 2020). Excessive or poorly controlled reactive oxygen species can alter proteins, fats and DNA (Sies and Jones, 2020). Wu and colleagues propose that increased hydrogen peroxide from astrocytes could make the environment around nearby neurones less supportive (Wu et al., 2025).

Their experiment did not show that astrocyte-derived hydrogen peroxide alone kills motor neurones in people. Its narrower achievement was to identify a measurable source of oxidative stress and connect it to a defined sequence in cultured astrocytes (Wu et al., 2025).

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A gatekeeper and an old antihistamine

The scientists next examined a protein that helps cells respond to stress and regulate communication between structures inside the cell. It is known as the Sigma-1 receptor, or Sigma-1R (Wu et al., 2025). Sigma-1R is found mainly where two of these structures meet: the endoplasmic reticulum, a network that helps make proteins and fats and stores calcium, and the mitochondria, which generate much of the cell’s usable energy. At these contact points, Sigma-1R helps regulate the movement of calcium, communication between the two structures and the cell’s response to stress (Kourrich et al., 2012).

In the cell experiments, Sigma-1R interacted with p65 and reduced its movement into the nucleus (Wu et al., 2025). Within the maintenance-crew analogy, Sigma-1R behaved like a gatekeeper holding the alarm message outside the control room. Increasing Sigma-1R expression weakened the downstream response (Wu et al., 2025).

The researchers then used clemastine, an established antihistamine that also interacts with Sigma-1R. In cultured astrocytes, clemastine reduced NOX4 expression and hydrogen-peroxide production (Wu et al., 2025). A compound that blocks Sigma-1R weakened clemastine’s effect, supporting the interpretation that the receptor was involved (Wu et al., 2025).

It is an interesting result and an easy one to oversell. Clemastine was tested in cultured astrocytes, not in people with ALS, and the study did not establish a safe human dose capable of reproducing the cellular effect (Wu et al., 2025). It was not tested as a treatment in the study’s mice either (Wu et al., 2025). Here, clemastine is best understood as an experimental probe: it helped the researchers test whether influencing Sigma-1R altered the pathway.

The animal experiments supplied another layer of evidence. The researchers used a modified viral delivery system called adeno-associated virus 9 (AAV9) to make neurones in newborn mice produce a 42-repeat version of poly-PR. They then compared mice with normal Sigma-1R against mice genetically engineered to lack the receptor (Wu et al., 2025). Mice without Sigma-1R showed greater astrocyte activation, increased NOX4 expression, stronger evidence of nerve-cell damage and loss, and poorer survival (Wu et al., 2025).

The result fits the proposed protective role of Sigma-1R within this particular model. Yet removing a receptor genetically from a mouse is far removed from treating ALS after symptoms begin. The model captures selected features of C9orf72-associated disease, not the full complexity of human ALS (Wu et al., 2025).

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Crossing the gap to people

Cell cultures, mice and patients provide different kinds of evidence. Cultured cells allow researchers to observe a molecular sequence in detail, while animal models show how selected processes behave within a living nervous system. Neither can establish on its own that the same mechanism drives human disease.

The central limitation identified at the beginning therefore remains unresolved. The complete route from poly-PR entering the astrocyte, through p65 and NOX4, to increased hydrogen peroxide has not been demonstrated in people with C9orf72-associated ALS (Wu et al., 2025).

There is some related patient-derived evidence. In a 2019 study, researchers took donated cells from people with C9orf72-associated ALS and reprogrammed them into a flexible state from which different cell types can be produced. These adaptable cells are called induced pluripotent stem cells, or iPSCs (Birger et al., 2019).

The researchers guided the iPSCs into becoming astrocytes. Those patient-derived astrocytes showed increased oxidative stress and were associated with reduced motor-neurone survival when the two cell types were grown together (Birger et al., 2019). This strengthens the broader case for astrocyte dysfunction in C9orf72-associated ALS, but it does not confirm the precise sequence described by Wu and colleagues.

Sigma-1R also comes with an awkward piece of clinical evidence. A medicine intended to activate this receptor, called pridopidine, has already been tested in people with ALS in the HEALEY ALS Platform Trial (Writing Committee for the HEALEY ALS Platform Trial, 2025). In the main 24-week analysis, there was no statistically significant difference between pridopidine and placebo on the combined assessment of functional decline and survival, and no benefit appeared on the other principal measurements in the overall trial population (Writing Committee for the HEALEY ALS Platform Trial, 2025).

A later post hoc analysis reported apparently favourable findings among a selected subgroup of participants with definite or probable ALS, disease onset within 18 months and rapid progression (Geva et al., 2026). This analysis was carried out after the main trial results were known. Because the researchers examined a selected subgroup and made multiple comparisons, the findings are useful for generating a hypothesis rather than confirming a treatment benefit. They do not overturn the negative result of the trial’s main analysis (Geva et al., 2026).

Pridopidine and clemastine are different medicines, so one negative trial cannot settle every question about Sigma-1R. Even so, the HEALEY result belongs in this story. It is a reminder that an elegant cellular mechanism may be real without becoming a useful treatment.

The wider astrocyte field offers similar warnings. Rojas and colleagues found that substances released by mutant-SOD1 astrocytes triggered electrical overactivity, calcium influx and mitochondrial disruption in motor-neurone cultures. This was followed by the production of reactive oxygen and nitrogen chemicals, activation of a cell-death signalling protein called c-Abl, and motor-neurone death (Rojas et al., 2015).

Pehar and colleagues tested an antioxidant enzyme directed towards mitochondria, the internal structures that generate much of a cell’s usable energy. In cultures of astrocytes carrying a specific mutant form of human SOD1, the intervention improved antioxidant defences and mitochondrial function while reducing toxicity towards co-cultured motor neurones (Pehar et al., 2014). In mutant-SOD1 mice, however, it did not delay disease onset or extend survival (Pehar et al., 2014).

Another study examined a signal-and-receptor pair capable of activating a cell-death process. The signal is called tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and the receiving protein is known as death receptor 5 (DR5). In experimental SOD1 systems, astrocyte-derived TRAIL activated DR5 on motor neurones and contributed to cell death; antibodies that neutralised DR5 reduced the injury (Yang et al., 2025). This is an early mechanistic finding, not evidence that targeting TRAIL and DR5 is an effective treatment for people with ALS.

These proposed routes need not exclude one another. A failing support cell may develop several harmful behaviours, and the dominant combination may differ between forms of ALS.

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What makes this frontier science?

The Wu study is strongest where it is most specific. It provides experimental evidence that poly-PR can enter astrocytes and connects that event with p65 movement, increased NOX4 expression and increased hydrogen peroxide. It also presents evidence that Sigma-1R can restrain parts of this response in cultured cells and influence disease severity in the mouse model (Wu et al., 2025).

The unanswered questions are equally specific. Researchers still need to establish how poly-PR enters astrocytes, whether the full pathway appears naturally in patient-derived cells and whether it can be detected in relevant human tissue. They must also discover whether interrupting it after disease-related changes have begun protects motor neurones. Each stage should be tested independently. Preventing poly-PR uptake could show whether entry into the astrocyte is necessary. Reducing NOX4 could reveal how much of the oxidative response depends on that enzyme. Altering Sigma-1R after symptoms appear would provide a more realistic test of therapeutic potential.

Negative findings would be valuable. They could show that one step accompanies the damage without driving it, or that a striking mechanism in a simplified model has little influence in human cells. Frontier research advances by exposing an appealing explanation to harder experiments, not by protecting it from doubt.

The study has not identified the single cause of ALS, nor has it produced a treatment. Its contribution is more focused: it connects an abnormal C9orf72-associated protein with a specific change in the behaviour of neighbouring astrocytes (Wu et al., 2025). If the same chain is active in people, it could help to explain how a disturbance beginning in one cell recruits neighbouring support cells into the disease process. That possibility changes the question. Instead of asking only why a motor neurone fails, researchers can also ask what has happened to the cells responsible for keeping it alive.

For patients and families, biological understanding often arrives long before treatment. Yet treatments cannot be designed intelligently without identifying which processes are driving the disease, where they begin and how they spread. This research gives investigators a more detailed map of one possible route. The next task is to establish whether that route is genuinely active in human ALS. If it is, researchers must then determine whether closing it can protect the motor neurones that depend on the cell next door.

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How can You Nutrition Clinic help

Understanding what the science says is only part of it. Translating it into something useful for your body, at this point in your journey, is where clinical experience matters.

At You Nutrition Clinic, Dr Kirstie Lawton and her specialist MND/ALS team follow research like this closely. Not to endorse every finding as a ready-made intervention, but to understand the mechanisms, track the evidence as it develops, and consider how emerging science might inform the work they do with each client.

Our approach combines a thorough clinical history with functional testing, examining oxidative markers, mitochondrial function, gut health, inflammation and nutrient status, to build a protocol shaped around your body and your presentation. That protocol is reviewed and adapted regularly as your needs change, woking with you and your medical team.

Because no two presentations of MND/ALS are the same, every client receives a bespoke programme. The science informs the thinking. The testing shapes the protocol. The goal is individualised support, grounded in evidence

Learn more and book a consultation at You Nutrition Clinic →

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Stay curious. Stay hopeful. Support your brain. 🧠

Disclaimer: This article is for informational and educational purposes only and does not constitute medical advice. Always consult with a qualified, registered medical doctor (MD) for diagnosis and treatment decisions.

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References

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Birger, A. et al. (2019). Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity. EBioMedicine, 50, 274–289. https://doi.org/10.1016/j.ebiom.2019.11.026

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Di Giorgio, F. P. et al. (2007). Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nature Neuroscience, 10, 608–614. https://doi.org/10.1038/nn1885

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