Part 1 of 4: why the copper story in ALS/MND is more complicated than “too much” or “too little”
Most conversations about nutrients and neurological disease follow a familiar logic: too little of something good, or too much of something harmful. The copper story in amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), does not fit this pattern.
Copper in ALS is not simply elevated or depleted. In some contexts it appears in the wrong place, bound to the wrong proteins, or unavailable to the structures that need it most. Understanding why requires some background on a protein called superoxide dismutase 1, or SOD1.
This blog is written for anyone curious about the science, including people living with ALS or supporting someone who is. The biology here is genuinely complex, and the purpose is not to suggest that understanding it leads to any straightforward action. It is to describe what the research actually shows.
This is the first in a four-part series on metals and motor neurone disease. Part 2 turns to zinc and iron. Part 3 explores copper, ceruloplasmin and your genes: Morley Robbins' theory of copper dysregulation, the ATP7B gene linked to Wilson disease, and what the LifecodeGX Metals and Minerals nutrigenomic panel can reveal about individual copper handling. Part 4 follows a patient with primary lateral sclerosis (PLS) whose diagnostic journey raises questions about copper metabolism and its genetic basis.
The protein at the centre of this story
In 1993, a team led by Daniel Rosen published a paper that changed the course of ALS research. They identified mutations in a gene encoding an enzyme called superoxide dismutase 1 (SOD1) in families with hereditary ALS. (Rosen et al., 1993) It was the first genetic cause of ALS ever identified.
SOD1's job is to dismantle a toxic byproduct of normal cell metabolism called superoxide: a reactive form of oxygen that, if left to accumulate, can damage proteins, fats and DNA inside the cell. SOD1 converts superoxide into hydrogen peroxide and ordinary molecular oxygen, a process called dismutation. It does this so efficiently that it accounts for most of this clean-up work inside cells. (Wright et al., 2019)
The body makes three distinct superoxide dismutase enzymes, each working in a different location. SOD1 operates primarily inside the cell's fluid compartment (the cytosol). SOD2 (superoxide dismutase 2) works inside the mitochondria, the structures that generate most of a cell's energy. SOD3 (superoxide dismutase 3) works outside cells entirely, in the connective tissue and fluid that surrounds them (Zelko et al., 2002). Each covers different ground.
To do its job, SOD1 requires two metals: copper and zinc. These are built directly into the protein's structure. Copper sits at the active site, the region where the actual chemistry of dismutation happens. It is the working metal. Zinc plays a different role: it holds the three-dimensional shape of the protein together, keeping one of its loops in the correct position. If copper is the machinery, zinc is the scaffolding (Wright et al., 2019).
Without copper, SOD1 loses its normal catalytic activity. Loss of zinc destabilises its structure and makes partial unfolding and aggregation more likely.
Thirty years of mutations
Since 1993, researchers have catalogued more than 200 distinct mutations in the SOD1 gene linked to ALS (Huang et al., 2024). Their frequency varies by population, accounting for approximately 12 per cent of familial ALS and about 1–2 per cent of apparently sporadic ALS (Huang et al., 2024; Akçimen et al., 2023).
For three decades, a central question has been: what do these mutations actually do? The current view is that they do not primarily cause disease by stopping SOD1 from working. Many SOD1 mutants retain some enzymatic activity. Instead, the mutations appear to give the protein new and harmful properties it would not otherwise have. Researchers call this toxic gain of function (Kaur et al., 2016; Huai & Zhang, 2019).
In practice, the mutant protein does not simply switch off. It can unfold, exposing parts of its structure that are normally tucked away. In this unfolded or partially misfolded state, mutant SOD1 can form abnormal, context-dependent interactions with numerous cellular proteins. These interactions may disturb mitochondrial function, protein quality control, axonal transport and RNA processing, although only a subset of proposed partners have been confirmed as direct and biologically important interactions (Huai & Zhang, 2019).
One further dimension complicates this picture. Misfolded forms of normal (non-mutant) SOD1 have been found in motor neurones and their supporting cells in people with sporadic ALS who carry no SOD1 mutation (Marlow et al., 2025). Whether the same toxic mechanism operates without a genetic trigger in this wider group is an active area of investigation.
The copper problem inside the protein
Here is where the copper story becomes specific to what happens inside the cell, rather than in the blood or diet.
When the body makes SOD1, the new protein is not immediately ready to work. Before it can process superoxide, it must acquire its copper and zinc, fold into its correct three-dimensional shape, form an internal disulphide bond that stabilises each subunit, and assemble into a dimer. This finishing process requires assistance from other proteins. (Wright et al., 2019)
Zinc is relatively straightforward: SOD1 can bind zinc on its own. Copper is different.
Cells keep free copper under tight control. Copper floating freely inside a cell is chemically reactive and can cause damage. Instead, the cell uses a relay system: intracellular copper is kept at extremely low, tightly buffered concentrations and is generally delivered through transporters, chaperones and other binding molecules. (Boyd et al., 2020) The protein responsible for delivering copper specifically to SOD1 is called CCS (copper chaperone for superoxide dismutase). CCS physically docks with SOD1, inserts copper into the active site, and helps complete the structural bond that stabilises the finished enzyme (Wright et al., 2019; Kawamata & Manfredi, 2010).
Several ALS-linked mutations weaken SOD1's ability to bind zinc correctly. When zinc is missing or poorly held, SOD1 tends to unfold. And CCS does not readily deliver copper to an unfolded protein. The cascade runs like this: a mutation impairs zinc binding, the protein begins to unfold, and CCS cannot complete its copper delivery because the receiving end is no longer the right shape. (Wright et al., 2019)
This sequence does not apply equally to every SOD1 variant; different mutations disrupt SOD1 maturation in different ways.
This is not about too little copper in the diet or in the blood. It is about copper failing to reach its specific destination inside a specific protein, because a mutation has changed the shape of what it is supposed to dock with.
There is a further consequence to losing zinc. When zinc departs and SOD1 begins to unfold, the copper that remains in the protein is no longer held in the correct position by the surrounding structure. In experimental systems, zinc loss can leave copper-containing SOD1 structurally disordered, making the copper centre more redox-reactive and capable of promoting damaging reactions, including protein tyrosine nitration (Trumbull & Beckman, 2009). This mechanism has been demonstrated in experimental settings and should not be taken as established for every person with SOD1-ALS.
A 2016 study in mouse models illustrated the copper delivery problem from a different angle. When human CCS was genetically over-expressed in ALS mice alongside the mutant SOD1 gene, the animals died within two weeks of birth. Co-expression of CCS and mutant SOD1 produced profound copper insufficiency within the spinal cord. The researchers proposed that the unusually high demand created by the two overexpressed proteins exceeded the tissue's available copper supply. When these mice were treated with a compound called CuATSM (diacetylbis(N4-methylthiosemicarbazonato)copper(II)), which can deliver copper directly into the nervous system, early death was prevented. Continued treatment extended average survival by 18 months. When treatment was stopped, ALS symptoms appeared within three months, and restarting treatment could rescue symptomatic mice (Williams et al., 2016). This was an unusual double-transgenic model with extreme copper demand, so the magnitude of the response should not be assumed to predict what CuATSM would do in ordinary SOD1-ALS or sporadic ALS. This is animal model data, with the substantial translational distance from mouse to human that always applies. But it illustrates clearly that the spinal cord's access to usable copper, not just the presence of the chaperone protein, shapes what happens to these cells.
Where mutant SOD1 accumulates in the cell
SOD1 is primarily a cytosolic enzyme, but a portion of it is found in another location: inside the mitochondria, specifically in a compartment called the intermembrane space.
Mitochondria are the structures that generate most of a cell's energy. They have two membranes, one nested inside the other, and the intermembrane space is the narrow gap between those two layers. It is a functional compartment: certain chemical reactions take place there, and the conditions within it differ from both the cell's cytosol and the interior of the mitochondrion. CCS and the Mia40/Erv1 disulphide-relay system help regulate the import, maturation and retention of a proportion of SOD1 within the mitochondrial intermembrane space. (Kawamata & Manfredi, 2010)
In experimental ALS models, mutant SOD1 can undergo abnormal mitochondrial import, retention and accumulation. Its misfolding and aggregation appear to alter the normally regulated process. (Tafuri et al., 2015; Magrané et al., 2009)
Experiments in which mutant SOD1 was deliberately targeted exclusively to the intermembrane space showed that this accumulation alone was sufficient to impair the mitochondrion's energy production, disrupt how the cell handles calcium, and cause motor neurones to degenerate over time, though the same study noted that mitochondrially targeted mutant SOD1 was not sufficient to reproduce a complete ALS phenotype. (Igoudjil et al., 2011) Earlier work in cell models found that mutant SOD1 in the intermembrane space caused mitochondria to fragment and sensitised cells to further metabolic and oxidative stress. (Magrané et al., 2009) In mouse models, early structural changes in mitochondria originate from the intermembrane space itself swelling and breaking down. (Higgins et al., 2003)
The picture is of a protein that, in its mutant form, ends up in a cellular compartment where it does not belong in normal quantities, and where its presence impairs the very structures that power motor neurons.
The geography of copper in ALS tissue
For a long time, research into copper and ALS focused mainly on the SOD1 protein itself. More recently, researchers have asked a different question: where, precisely, does copper sit in the nervous system, and does that geography shift in ALS?
A 2024 study examined spinal cord tissue from people with sporadic ALS (the most common form, which is not directly linked to SOD1 gene mutations) and compared it to tissue from people without ALS. (Hilton et al., 2024) The distribution of copper across different spinal cord regions was disrupted. Copper levels in the ventral grey matter, the region where motor neurones are most densely packed and where they are lost in ALS, were reduced compared to control tissue.
In the adjacent white matter, the pattern was different: copper appeared increased relative to control tissue rather than depleted (Hilton et al., 2024). This is not a picture of copper being globally low or globally high across the spinal cord. It is copper out of place: reduced where motor neurones are most densely packed, and elevated in surrounding white matter in ways whose significance remains unclear. This was an observational study of post-mortem spinal cord tissue from individuals at end-stage disease. Observations of this kind cannot determine whether any redistribution was a cause of disease progression, a consequence of it, or a compensatory response.
The same study found that the copper-dependent ferroxidase enzymes ceruloplasmin and hephaestin were increased at the protein level in ALS spinal cord, suggesting more enzyme was present, but proportionally less appeared to be functionally copper-loaded. SOD1 protein abundance and activity were unchanged in sporadic ALS tissue in the same study (Hilton et al., 2024). The copper-dependent enzymes were present, and actually increased, but their collective ferroxidase activity was impaired.
A separate study in mice bred to have reduced copper uptake throughout the central nervous system found lower motor neurone numbers even in the absence of any ALS mutation. The loss was not as severe as in ALS model mice and did not produce overt motor symptoms, but it suggests copper availability in the spinal cord has baseline relevance for motor neuron survival (Liddell et al., 2024).
An earlier study took a different approach: mice with an SOD1 mutation whose protein cannot bind copper, bred with mice that had a genetic copper deficiency, lived 9 per cent longer than those with normal copper carrying the same mutation. In that specific model, less available spinal cord copper slowed disease. (Kiaei et al., 2004)
These findings are not immediately consistent with one another: lower copper in the ventral grey matter in human ALS; a possible benefit from reducing copper in one mouse model; worse motor neurone survival with depleted copper in another. The relationship between copper and disease does not follow a simple line, and it shifts across different models, mutations and cellular contexts.
Blood copper: what the measurements show
Individual studies of blood copper in ALS have produced inconsistent results. Some have reported lower plasma copper concentrations in people with ALS, others have found higher levels, and others have found no meaningful difference. A 2023 systematic review and meta-analysis of 29 studies found no statistically significant difference in serum or plasma copper concentrations between people with ALS and controls. (Kamalian et al., 2023)
Blood copper measurements do not reflect copper within motor neurones, within SOD1, or within mitochondrial compartments. These are different pools, separated by transport systems that a blood test cannot capture. A person with normal plasma copper could have disrupted copper handling inside their cells; a person with lower plasma copper could have intact cellular copper metabolism. Current evidence does not support serum or plasma copper as a reliable biomarker of ALS-associated copper redistribution.
Where this leaves things
Across the evidence described here, a picture emerges of copper whose role in ALS is less about how much is circulating and more about where it sits within specific proteins and cellular structures, and whether it can reach them.
SOD1 without catalytic copper cannot perform its normal superoxide-dismutase reaction, although loss of this activity is not considered the principal cause of SOD1-ALS. SOD1 without its zinc is more likely to misfold, which makes copper delivery harder. Mutant SOD1 that accumulates in the mitochondrial intermembrane space damages energy production. The distribution of copper across the ALS spinal cord appears disrupted in ways that vary by region and do not follow any simple pattern.
The copper story in ALS turned out to be stranger than the standard nutrient logic suggests: not simply elevated or depleted, but displaced, bound to the wrong proteins, and sometimes unavailable to the structures that need it most. Part 2 of this blog series takes the disruption further, into zinc, iron, and a form of cell death that researchers only named in 2012. Part 3 looks at copper, ceruloplasmin and your genes, explains Morley Robbins' theory of copper dysregulation, the ATP7B gene associated with Wilson disease, and how the clinic uses nutrigenomic testing to understand how well each person handles copper. Part 4 follows a patient with primary lateral sclerosis (PLS) whose symptoms may relate to genetic copper dysfunction, drawing on what this series has established and asking what happens when these questions stop being theoretical. Each post holds one thread. Together, they pull on something bigger.
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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