Part 2 of 4: Zinc, Iron and the metals that won't stay in their lane
Part 1 of this series examined the biology of superoxide dismutase 1 (SOD1), the role of copper and zinc within that protein, and what researchers have found when they map the distribution of copper across the spinal cord in amyotrophic lateral sclerosis (ALS), also called motor neurone disease (MND). If you have not read Part 1, it provides the context for much of what follows.
This blog takes the metals story into three new territories: zinc, which performs a structural role within SOD1 but becomes abnormally distributed in experimental ALS models; iron, whose presence in the spinal cord is increasingly linked to a specific form of cell death; and the question of how copper, zinc and iron interact with one another in ways that make the picture considerably more complicated than any single-metal analysis can capture.
The governing message remains the same as in Part 1: the relationship between metals and motor neurone health in ALS is not a story of too much or too little of any one thing. It is a story about where metals are, what proteins they are bound to, and what happens when those bindings go wrong.
When zinc leaves the protein
Part 1 described how zinc performs a structural role within SOD1: it holds one of the protein's loops in the correct shape, allowing the enzyme to function and providing the platform on which copper can do its catalytic work. Several ALS-linked mutations weaken this zinc binding. Loss of zinc destabilises SOD1 and increases its tendency to partially unfold and aggregate.
The fate of that displaced zinc is not a trivial question.
In a study using mice expressing the ALS-linked G93A SOD1 mutation, researchers found something not observed in healthy mice: the accumulation of what the researchers called labile zinc in both neurones and astrocytes of the spinal cord. (Kim et al., 2009) Labile zinc means zinc present in a loosely bound, exchangeable pool rather than tightly incorporated into stable proteins. The distribution of this labile zinc correlated with the pattern of motor neuronw degeneration. It was not evenly distributed. It appeared where cells were dying.
The same study found that this accumulated zinc was associated with increased levels of a molecule called 4-hydroxynonenal (HNE), a compound that forms when cell membrane fats are damaged by oxidation and is itself toxic to cells. Exposure of spinal cord neurones to HNE increased intracellular zinc further, and exposure to zinc increased HNE production: a self-reinforcing cycle with potentially damaging consequences for the cells caught within it. When the researchers administered a zinc chelator (a compound that binds and removes loose zinc) to the transgenic mice, survival was extended. (Kim et al., 2009)
This is a difficult finding to interpret straightforwardly. Zinc chelation extended survival in one mouse model of ALS. But zinc is an essential metal with fundamental roles in hundreds of enzymes and regulatory proteins throughout the body. The experimental use of a chelator in a controlled model does not translate into any general conclusion about zinc intake or supplementation in people. The finding says something specific: that in this model, displaced labile zinc in the spinal cord contributed to a cycle of cellular damage. It does not say that zinc itself is harmful.
A separate line of research found that across multiple SOD1 mouse models, total spinal cord copper was increased, while the proportion incorporated into mutant SOD1 varied or was reduced, indicating an expansion of non-SOD1-bound copper pools. (Tokuda et al., 2013) Zinc was elevated alongside copper. These findings held across mutant forms with very different copper-binding abilities, suggesting the disruption reflects something common to mutant SOD1's interaction with the cell's metal-handling systems, not just the specific chemistry of any one mutation.
The cell's response: metallothioneins
When the spinal cord is under this kind of metallic pressure, it does not simply sit still. The cell can produce small proteins designed to bind and hold excess copper and zinc, sequestering them away from sensitive structures. These proteins are called metallothioneins, and two forms called metallothionein-I (MT-I) and metallothionein-II (MT-II) are expressed throughout the body, including in the nervous system. A third form, metallothionein-III (MT-III), is found predominantly in the central nervous system, particularly the brain.
A 2006 study measured metallothionein levels in the spinal cords of G93A SOD1 mice alongside copper and zinc concentrations. (Tokuda et al., 2006) The researchers found that MT-I and MT-II were significantly elevated in ALS mouse spinal cords compared to controls, rising as disease progressed. At the same time, total zinc was elevated in the spinal cord at end-stage disease, while the copper incorporated into SOD1 itself was reduced despite the total spinal cord copper being elevated. Lipid peroxidation markers, which signal membrane fat oxidation, were also raised.
The picture the researchers described was not of a system overwhelmed without response. It was of a system trying to respond: metallothioneins rising as an apparent attempt to manage displaced copper and zinc, while at the same time evidence of ongoing oxidative damage accumulating. Whether the response was sufficient to protect cells, or represented the cell using one of its defences against a problem that ultimately exceeded it, is a question the data does not fully resolve.
What these studies show is that the distribution of copper within the spinal cord is altered: the proportion incorporated into SOD1's active site is reduced, non-SOD1-bound copper pools appear expanded, and metallothioneins are elevated, while overall copper and zinc concentrations are raised. The researchers measured different pools at a given point in time; they did not track individual metal atoms moving between locations. The picture is of metals present but displaced.
Zinc and TDP-43: a connection beyond SOD1
Most of the metals research in ALS began with SOD1, because that was the first genetic cause identified and because SOD1 directly binds copper and zinc. But the most common molecular feature of ALS is not SOD1 at all. The most common pathological signature in ALS is cytoplasmic accumulation of a protein called TDP-43 (TAR DNA-binding protein 43), found in approximately 97 per cent of cases overall. SOD1-associated and FUS (fused in sarcoma)-associated forms are notable exceptions and tend to have different dominant protein pathology (Mackenzie et al., 2007).
A 2010 study added an unexpected link between zinc and TDP-43. The researchers exposed neuronal cells in culture to a range of metals and oxidative stressors: copper, iron, hydrogen peroxide, and zinc. (Caragounis et al., 2010) Only zinc induced a specific and striking response: depletion of TDP-43 from the cell nucleus, followed by the appearance of TDP-43 aggregates in the cytoplasm. This pattern, a protein that normally functions in the nucleus leaving its proper location and clumping together in the cell's fluid compartment, is a defining feature of TDP-43 pathology in ALS tissue.
The effect was specific to zinc. Copper, iron and hydrogen peroxide did not replicate it in the same way. The doses required to trigger it were experimentally high, which places this finding firmly in the category of a laboratory observation in cells rather than evidence of a mechanism operating at physiological zinc concentrations in people. But the specificity of the finding is striking: one metal, in neuronal cells, producing the pathological hallmark of the most common molecular form of ALS.
This does not mean zinc causes ALS. The study was in cell culture, not in human tissue. What it does suggest is that zinc, when present at experimentally high concentrations in the wrong cellular compartment, can trigger one of the molecular changes most closely associated with ALS pathology. How that connects to the labile zinc findings in SOD1 mouse spinal cords, and whether these mechanisms interact in people with ALS, remains an open question.
Iron and the cell death question
Iron is the third metal whose behaviour in ALS has attracted sustained research attention. Its story connects to a relatively recently characterised form of regulated cell death called ferroptosis.
Ferroptosis is driven by iron-dependent damage to the fats within cell membranes. When iron is present in a reactive form inside the cell, it can trigger a chain reaction in which membrane fats are progressively oxidised. If the cell cannot adequately stop this chain reaction, the membrane is compromised and the cell dies. (Sun et al., 2022) The process is distinct from the forms of cell death most people have heard of, and it is specifically iron-dependent: without the iron, the chain reaction does not run.
The protein GPX4 (glutathione peroxidase 4) is one of the central cellular defences against ferroptosis. It converts toxic lipid peroxides into harmless alcohols, acting as a brake on this form of cell death.
A 2022 study examined post-mortem spinal cord tissue from people with both sporadic and familial ALS, alongside multiple mouse models. (Wang et al., 2022) The human tissue analysis involved a limited number of post-mortem samples, so those findings should be considered important but preliminary. Across both the human samples and the animal models, the researchers found that GPX4 was depleted in ALS tissue compared to controls. In the mouse models, this depletion appeared before the onset of visible motor symptoms. It was found across different genetic models, including those based on SOD1, TDP-43 and C9orf72 (chromosome 9 open reading frame 72) mutations, suggesting whatever disrupts GPX4 in ALS is not unique to one genetic background.
The same study generated mice engineered to produce extra GPX4 in spinal motor neurones. When these mice also carried the mutant SOD1 gene, disease onset was delayed, motor function was better preserved for longer, and lifespan was prolonged. The researchers attributed this protection to reduced lipid peroxidation and better motor neuron survival. (Wang et al., 2022) This is preclinical data in animal models. The translational distance from a mouse engineered to overexpress GPX4 to any therapeutic approach in people with ALS is substantial and uncertain.
Unlike copper and zinc, iron is not a cofactor of SOD1. Its relevance to ALS arises through wider processes, including iron transport and storage, blood-spinal cord barrier integrity, mitochondrial dysfunction, lipid peroxidation and ferroptosis. These pathways may amplify motor neuron injury, but current evidence does not establish whether iron dysregulation is an initiating cause, a downstream consequence, or both in different forms and stages of ALS.
Iron enters the ferroptosis picture because GPX4 depletion alone does not explain the full mechanism: iron is required to drive the lipid peroxidation that GPX4 ordinarily suppresses. One route by which excess iron may reach the spinal cord in ALS involves the blood-spinal cord barrier, the structural equivalent of the blood-brain barrier, which normally prevents blood-borne substances from entering spinal cord tissue. In ALS model mice, this barrier breaks down. (Winkler et al., 2014).
When the blood-spinal cord barrier is compromised, haemoglobin and the iron it contains can leak into spinal cord tissue. A 2014 study in SOD1-mutant mice showed that the accumulation of blood-derived haemoglobin and iron in the spinal cord contributed to early motor neuron degeneration, through a mechanism involving iron-dependent oxidative stress. When the researchers repaired the barrier or removed the blood-derived iron chemically, early motor neuron injury was reduced. (Winkler et al., 2014) The study itself noted that the role of blood-spinal cord barrier breakdown in human ALS remains unclear.
This suggests that in at least some ALS contexts, the iron problem may be specifically about iron arriving in the spinal cord in an abnormal form, through a damaged barrier, where it then contributes to a damaging process, rather than the body containing too much iron overall.
The picture in human ALS is more complex still. A 2025 study measuring blood levels of multiple metals and biochemical markers in 121 people with ALS found that higher blood iron and higher serum ferritin were associated with greater disease severity. (Xie et al., 2025) Ferritin is an iron-storage protein commonly used when assessing iron status, but it also rises during inflammation and in several other medical conditions. A higher result does not by itself establish iron overload. The association between ferritin and disease severity in this study held after accounting for age and other factors. Higher blood iron was more pronounced in men and in those with spinal-onset disease. But this is a cross-sectional study: it shows a relationship between iron-related markers and disease severity at a single point in time, not a causal chain. It cannot tell us whether elevated iron contributes to faster disease progression, or whether more severe disease is associated with changes in how the body handles iron.
The metals do not operate alone
The biological reality in ALS is that copper, zinc and iron do not behave as independent variables. The same cellular environments that handle one metal also regulate others. Several studies have found that disruption in one metal's distribution tends to be accompanied by disruption in others.
A 2021 review proposed a framework for thinking about ALS in which imbalances across multiple metals (copper, zinc, iron and manganese) interact with mitochondrial dysfunction across different regions of the nervous system, and this interaction, rather than any single-metal deficit or excess, drives the cascade of events leading to motor neuron loss. (Nakagawa & Yamada, 2021) In this model, the sensory ganglia, the spinal cord and the brain stem are all sites where metal disruption and mitochondrial failure compound each other. This remains a proposed model rather than an established causal account.
What the experimental data shows, when taken together, is that the distribution and binding state of each metal is not independent of the others. Labile zinc increases in some SOD1 models, but its precise source, including how much originates from SOD1 versus other cellular stores, has not been established. Copper is distributed differently across mutant SOD1 models, with expanded non-SOD1-bound pools alongside elevated overall concentrations. Iron that enters through a compromised blood-spinal cord barrier interacts with lipid peroxidation systems that GPX4 ordinarily suppresses. Each metal's disruption creates conditions that affect the others.
What the experimental research is exploring
Several approaches to modifying metal handling in ALS have shown effects on disease markers and survival in animal models. It is worth being clear about where this research currently stands.
A compound called CuATSM (diacetylbis(N4-methylthiosemicarbazonato)copper(II)), which can be taken orally and crosses the blood-brain barrier, has been studied extensively in SOD1 mouse models. (Soon et al., 2011) Its mechanism appears to involve delivering copper to cells under oxidative stress, as well as reducing a specific form of protein damage caused by reactive nitrogen species. CuATSM progressed through a small open-label Phase 1 study and a randomised Phase 2/3 trial. The Phase 2/3 trial was completed in 2021, but its outcomes have not been publicly reported. (International Alliance of ALS/MND Associations, 2026) Consequently, there is currently no substantiated clinical evidence that CuATSM benefits people with ALS, despite encouraging results in preclinical models.
Approaches targeting the ferroptosis pathway, including strategies to increase GPX4 activity or expression, are under preclinical investigation following the findings described above. (Wang et al., 2022) This work has not advanced to human clinical trials.
Zinc chelation in mouse models has extended survival in one study, (Kim et al., 2009) as has chelation of excess copper using a separate compound, which also slowed disease progression and reduced motor neuron loss in SOD1 mice even when treatment began after disease onset. (Tokuda et al., 2013) Both remain at the preclinical stage.
Iron chelation to address barrier-derived iron accumulation has been studied in ALS mice. (Winkler et al., 2014) One pilot study enrolled 23 people with ALS to investigate the iron chelator deferiprone. It reported acceptable safety without anaemia over 12 months and some changes in imaging and biochemical markers, but was not adequately powered to establish clinical efficacy. (Moreau et al., 2018) Current evidence does not support iron chelation as a proven treatment for ALS.
None of this research supports conclusions about dietary intake of any of these metals, or about supplementation. The interventions studied are specific compounds used in controlled experimental settings or formal clinical trials. They are not analogous to dietary zinc, dietary iron, or copper supplements.
What this means in practice
The research in this series describes biology at the level of individual proteins, cellular compartments and animal models. This section explains some concepts that arise in conversations about metals and ALS, and why the research findings cannot be directly translated into guidance about diet or supplementation.
Genuine copper deficiency is a distinct clinical condition
Copper deficiency is uncommon in most populations, but it does occur. It most commonly arises after gastric surgery or in people with conditions that reduce gut absorption. It has also been documented in people who take very high doses of zinc supplements over sustained periods. Zinc and copper share absorption pathways in the intestine. High zinc intake can induce a protein called metallothionein in intestinal cells that preferentially binds copper rather than zinc, reducing how much copper enters the bloodstream. Prolonged copper depletion can cause a neurological syndrome involving spinal cord dysfunction, sensory loss and peripheral neuropathy.
This condition, copper-deficiency myelopathy, produces some features that can superficially resemble aspects of ALS, because both affect motor and sensory pathways. They are distinct conditions. Clinical features include weakness, numbness and tingling, impaired balance and difficulty walking; anaemia, which can cause fatigue; and neutropenia, which increases susceptibility to infection. (Kumar, 2006) Copper deficiency is associated with measurably low blood copper and low caeruloplasmin (a copper-carrying enzyme in the blood), and the neurological features may stabilise or partially improve when copper status is restored. Sensory loss, gait ataxia and blood-count abnormalities are not defining features of classical ALS and may prompt investigation for a mimic or a coexisting deficiency. ALS is a neurodegenerative disease that does not respond to copper replacement. Neurological recovery after treatment can be incomplete, even when blood abnormalities improve (Kumar, 2006).
What blood tests measure and what they cannot
Several blood measurements are discussed in the context of metals and neurological health. Understanding what each represents, and where its limits lie, helps make sense of what this research does and does not show.
Serum copper estimates copper in the circulating blood compartment, most of which is associated with caeruloplasmin. As the meta-analysis described in Part 1 found, serum copper does not meaningfully differ on average between people with ALS and controls. It also cannot reflect copper levels within individual cells, within the mitochondrial intermembrane space, or within specific proteins such as SOD1. A normal serum copper does not confirm that copper is reaching SOD1 correctly; an abnormal value does not necessarily reflect intracellular copper handling.
Caeruloplasmin is a copper-containing enzyme that accounts for most copper in blood. It is also an acute-phase reactant, meaning its level can rise during inflammation independently of copper status.
A full blood count can identify the anaemia and neutropenia characteristic of copper-deficiency myelopathy. C-reactive protein (CRP) is a marker of inflammation; because both copper and caeruloplasmin can rise during inflammation independently of copper status, a CRP measurement helps contextualise those results.
Serum zinc is an imperfect and context-sensitive marker. It can be affected by recent food intake, fasting status, time of day, inflammation and albumin levels, and it does not show how zinc is distributed within the nervous system. (Wieringa et al., 2015)
Serum ferritin is an iron-storage protein often used when assessing iron status. As described above, ferritin also rises during inflammation, infection and liver disease. A higher result does not establish iron overload.
Transferrin saturation reflects the proportion of the iron-transport protein transferrin that is carrying iron. It gives information about iron availability in the bloodstream, not about iron at the level of individual cells or cellular compartments.
None of these measurements captures what the research in this series is actually about: the distribution of metals within specific proteins, the copper reaching SOD1's active site, the labile zinc in spinal cord neurons, or the iron entering through a compromised blood-spinal cord barrier. The gap between what a blood test measures and what is happening inside motor neurons is fundamental, and it runs through this series.
Why the research findings do not support supplementation or chelation
The experimental interventions described here, including zinc chelation, copper delivery via CuATSM and iron chelation using deferiprone, are specific compounds studied in controlled conditions at doses calibrated to the experimental setting. They are not dietary metals, and their effects in carefully controlled models cannot be generalised to the effects of dietary changes or supplements.
High-dose zinc supplementation can itself deplete copper, through the mechanism described above. Supplementing iron in the absence of documented iron deficiency carries its own risks. In ALS, the use of metal-chelating drugs remains experimental and should not be attempted outside qualified medical care or a formal clinical study. Some chelators have established uses for specific diagnosed metal-overload disorders, but that does not make them appropriate ALS treatments.
The research described here is a window into biology. It is not a roadmap to self-treatment.
What the picture looks like from here
Taken together across the first two parts of this series, the metals research in ALS describes a nervous system in which the distribution, binding and availability of copper, zinc and iron are all disrupted, in ways that interact with each other and with the biology of specific proteins and cellular structures.
The disruptions are not uniform across all forms of ALS. They vary by genetic background, by which region of the nervous system is examined, and by the stage of disease. The degree to which findings in mouse models reflect what happens in people with ALS is not always clear. The human tissue data is valuable but limited by the difficulty of obtaining and studying post-mortem spinal cord at multiple disease stages.
What is not supported by this body of evidence is a simple relationship between blood or dietary levels of any of these metals and ALS risk, progression or outcome. The question that runs through this series so far is whether the metals story in ALS concerns distribution, delivery and protein binding rather than overall quantity. Taken together, the research suggests that copper, zinc and iron handling may be disrupted in particular ALS tissues, disease subtypes and experimental models. It does not establish that all three metals are abnormal in every person with ALS.
That is a harder problem than a deficiency to correct. It is also a more precise description of the biology.
Coming up in Part 3: Copper, caeruloplasmin and your genes
The first two parts of this series have looked at what happens to metals inside the spinal cord. Part 3 steps back to ask how the body absorbs, carries and clears copper in the first place, and what our genes have to do with it.
It will look at caeruloplasmin, the protein that carries most of the copper in blood, and at the ideas of Morley Robbins, whose Root Cause Protocol places copper and caeruloplasmin at the centre of a wide range of health problems. His theory has a large following, particularly online, and Part 3 will set out what it proposes alongside what the published research does and does not support.
It will also explore ATP7B (ATPase copper transporting beta), the gene linked to Wilson disease, a rare inherited condition in which copper builds up in the liver and brain because the body cannot clear it properly. Low caeruloplasmin is one of the features used to diagnose it, which makes it a useful starting point for understanding how copper handling can go wrong. Finally, Part 3 will cover the ATP7B variants included in the Lifecode GX Metals and Minerals nutrigenomic panel: what a result from a test like this can tell you about copper handling, and where its limits lie.
Part 4 will bring these questions into the consulting room, through the case of a client living with primary lateral sclerosis (PLS), a rarer, slowly progressing condition related to ALS that affects the upper motor neurones. It will follow how questions about copper metabolism and its genetic basis are explored in practice, and what can and cannot be concluded for one individual.
Supporting MND and ALS at You Nutrition Clinic
Dr Kirstie Lawton, PhD, MSc, FBANT, founder and Clinical Director of You Nutrition Clinic, leads a dedicated multidisciplinary team supporting people living with Motor Neurone Disease, Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis. Kirstie heads up the MND/ALS/PLS team alongside Kerry (RNTP), Deborah (RD) and Rachael (RN), with further support from Rae, our breath and movement practitioner. Together the team brings clinical nutrition, dietetics, nursing and movement support under one roof, with specialist experience in the particular nutritional and functional challenges that MND /ALS presents.
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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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