When the wiring frays: where choline may fit in ALS

Richard Moore
Apr 22
12 min read

In the first article in this series, we looked at choline as a quiet but foundational nutrient. It helps cells communicate, helps build membranes, and helps support some of the chemistry cells use to stay organised under stress (Burns et al., 2025; van der Veen et al., 2017). That was the wide-angle view.

Now we narrow the lens.

Because if choline becomes genuinely interesting anywhere in neurodegeneration, it is here, in amyotrophic lateral sclerosis (ALS).

ALS is often described in stark, simple terms as a disease in which motor neurones die. That is true, but it is also incomplete. Under the surface, ALS looks less like one switch being turned off and more like several systems losing stability at once. Signalling becomes less reliable. Membranes become more fragile. Mitochondria struggle to keep up. Oxidative stress rises. Calcium control slips. Inflammation lingers where it should not. The damage is not tidy, and it is rarely confined to one compartment of the cell (Cheng et al., 2025; Davis et al., 2023; Herrando-Grabulosa et al., 2021).

That is why choline keeps appearing in the ALS literature.

Not because it has been proven to “treat ALS”. It has not. But because it touches several of the same weak points the disease seems to expose. It sits near the messaging system, near the membrane, near the mitochondria, and near some of the pathways that govern stress and survival inside the cell (Burns et al., 2025; Herrando-Grabulosa et al., 2021; van der Veen et al., 2017).

This is the second in a 3-part series on choline and neurodegeneration. We split it into three parts because squeezing all of this into one article would flatten the science and lose the story. Part 1 laid the groundwork. This piece focuses on ALS mechanisms. Part 3 will move into the practical questions around food, testing, supplements, and where caution is needed.

ALS is not just cell loss. It is system failure in slow motion

A motor neurone is a remarkable cell. It can extend extraordinary distances, maintain constant communication with muscle, manage a huge transport burden, and meet heavy energy demands day after day. That makes it powerful, but it also makes it vulnerable. When the internal support systems begin to falter, motor neurones do not have much margin for error (Davis et al., 2023; Guedes-Dias & Holzbaur, 2019).

One way to picture ALS is to imagine a city whose power grid, road surface, signal network, and repair crews all begin failing at the same time. Traffic becomes chaotic, blackouts spread, and the damage starts to feed on itself. That is closer to the biology than the idea of one isolated defect.

Dr Kirstie Lawton (PhD), Director of You Nutrition Clinic, recently led the scoping review on which this blog series is based. Reviewing 55 papers, the study identified a set of recurring themes in ALS research: cholinergic dysfunction, phospholipid membrane impairment, mitochondrial dysfunction, calcium dysregulation, glutamate excitotoxicity, oxidative stress, neuroinflammation, and metabolomic disruption. Its conclusion was careful, but hard to ignore: these are all recognised drivers of ALS pathogenesis, and all may be influenced by choline deficiency through impaired acetylcholine synthesis and reduced phosphatidylcholine availability.

That word may matters. It keeps the piece honest.

The first crack may be in the messaging system

Choline’s best-known neurological role is that it helps the body make acetylcholine, one of the chemical messengers used in nerve signalling and muscle control (Burns et al., 2025; Davis et al., 2023). In ALS, that matters because the motor system depends on exquisitely timed communication. If the signalling is compromised early, it may not just reflect damage. It may help shape it.

Casas et al. (2013) found early presymptomatic cholinergic dysfunction in the spinal cord of SOD1(G93A) mice, including reduced choline acetyltransferase content in motor neurones and cholinergic interneurons before overt denervation markers had fully emerged. In other words, part of the messaging apparatus looked disturbed before the system had visibly collapsed. Fil et al. (2017) reported reduced choline acetyltransferase expression in a profilin-1 mutant mouse model that also showed mitochondrial fragmentation, glial activation, muscle atrophy, and reduced survival. Taken together, those studies suggest that cholinergic disruption may be part of the early ALS story rather than merely a late echo of neurone death (Casas et al., 2013; Fil et al., 2017).

That does not prove dietary choline deficiency causes ALS. It does support a more nuanced point: if choline supply or choline handling is compromised, a system that already depends on cholinergic precision may become even less resilient.

The membrane is not scenery. It is part of the plot.

This is where the story gets deeper.

Choline is needed to make phosphatidylcholine, one of the major phospholipids in cell membranes (Burns et al., 2025; van der Veen et al., 2017). That matters because membranes are not passive wrappers. They are active, intelligent surfaces. They help determine what enters the cell, how receptors behave, how signals move, how organelles communicate, and how damage is contained or amplified (Falabella et al., 2021; van der Veen et al., 2017).

If you want a non-technical analogy, think of a membrane as a building’s outer wall combined with its electrical insulation and part of its security system. If that layer is unstable, everything inside becomes harder to protect.

This is one reason lipid biology keeps surfacing in ALS research. Falabella et al. (2021) describe lipid homeostasis as central to cellular metabolism and note that abnormal lipid profiles are reported across neurodegenerative disease, including ALS. Dr Kirstie Lawton's (PhD) scoping review similarly mapped phospholipid membrane defects as a major ALS-related theme and highlighted evidence that choline deficiency in ALS models is associated with membrane abnormalities (Scoping review, 2026; Dučić et al., 2019; Falabella et al., 2021).

That matters because once membranes start to fray, the trouble does not stay politely in one place. Membrane instability can disrupt receptor function, calcium handling, organelle contact points, mitochondrial performance, and inflammatory signalling. One weak layer can destabilise the next.

Calcium control may be one of the hidden pressure points

Calcium is essential to life, but it is tightly managed because too much of it in the wrong place can become destructive. In neurones, calcium helps trigger signalling and muscle-related events. But when calcium handling becomes dysregulated, the same ion that helps communication can begin to drive stress, dysfunction, and cell death (Davis et al., 2023; Herrando-Grabulosa et al., 2021).

This is where Sigma-1 receptor, often shortened to Sig-1R, becomes especially interesting. Sig-1R is a small but influential protein found at the endoplasmic reticulum and particularly at the contact zones where the endoplasmic reticulum and mitochondria sit close together. Those contact zones are sometimes called mitochondria-associated membranes, or MAMs. If that sounds technical, the simplest way to think of MAMs is as docking stations where two important cell compartments exchange information and coordinate stress responses (Herrando-Grabulosa et al., 2021; Liu & Yang, 2022).

Brailoiu et al. (2019) showed that choline can act as an endogenous agonist of Sig-1R, helping potentiate intracellular calcium signals. Casas et al. (2013) also reported loss of Sig-1R presence in ALS mice alongside early cholinergic dysfunction. This does not yet give us a clean clinical message, but mechanistically it is fascinating. It raises the possibility that choline is not only a nutrient used to build molecules. It may also act as part of the cell’s internal signalling language in a region already implicated in ALS vulnerability (Brailoiu et al., 2019; Casas et al., 2013; Herrando-Grabulosa et al., 2021).

In plain English, choline may be relevant not only to what the cell is made of, but to how it keeps its internal conversations under control.

Then come the mitochondria, and the energy story darkens

Mitochondria are often lazily called the “powerhouses” of the cell. The phrase is overused, but the basic point is true. They convert fuel into usable energy, regulate parts of calcium balance, influence oxidative stress, and help determine whether a cell can survive pressure or starts sliding toward death (Falabella et al., 2021; Keethedeth & Anantha Shenoi, 2025).

Motor neurones are especially dependent on this machinery. They are long, busy, and expensive to run. If mitochondrial function falters, they do not have much slack in the system (Cheng et al., 2025; Herrando-Grabulosa et al., 2021).

Why does choline matter here? Because phosphatidylcholine is one of the major phospholipids in mitochondrial membranes, and membrane composition influences how well mitochondria maintain structure, electron transport, and energy production (van der Veen et al., 2017; Falabella et al., 2021). In choline-deficient animal work outside ALS, Hensley et al. (2000) found impaired complex I-linked respiration and increased hydrogen peroxide generation in mitochondria, suggesting that disturbed phosphatidylcholine metabolism can impair mitochondrial function and increase oxidative burden. In ALS models, Dučić et al. (2019) reported decreased choline in ALS-model astrocytes alongside altered mitochondria and higher sensitivity to oxidative stress. None of this proves cause and effect in humans with ALS, but it does build a plausible mechanistic bridge between choline biology and one of the core pathophysiological themes of the disease (Dučić et al., 2019; Hensley et al., 2000).

Oxidative stress may not just mark injury. It may help drive it.

Oxidative stress is one of those terms people hear often and understand only vaguely. The easiest way to think about it is as chemical wear and tear that builds when damaging reactive molecules outpace the cell’s defences. When that happens, proteins, DNA, and lipids can all be harmed (Dong & Yong, 2022; Perluigi et al., 2012).

In ALS, oxidative stress has been reported in spinal cord tissue, cell models, and transgenic animals, and one especially important consequence is damage to membrane lipids. Dong and Yong (2022) highlight oxidised phosphatidylcholines, often shortened to OxPCs, as potentially important mediators of neurodegeneration rather than mere by-products. If you want an analogy, OxPCs are not just the smoke after the fire. They may become part of what keeps the fire burning.

That idea has become even more intriguing in newer ALS-related work. Gomes-Duarte et al. (2025) reported that oxidised phosphatidylcholines contribute to pathological phenotypes in SOD1-associated ALS models and that neutralising them could blunt downstream damage. That does not mean “more choline equals more harm.” It means membrane lipid chemistry in ALS is complex, and once phosphatidylcholine becomes oxidised, it may shift from a structural necessity to a contributor to injury (Dong & Yong, 2022; Gomes-Duarte et al., 2025).

This is exactly why oversimplified nutrition messaging can become misleading. In biology, the same pathway can protect in one context and aggravate in another.

Inflammation is not just background noise either

ALS is not purely a neurone problem. It is also a glial and immune problem. Microglia, astrocytes, cytokines, and inflammatory signalling all appear to shape the environment in which motor neurones either cope or fail (Herrando-Grabulosa et al., 2021; Holbrook et al., 2021).

Choline intersects with this terrain in a few ways. Dr Kirstie Lawton's (PhD) scoping review flagged altered choline metabolite levels on magnetic resonance spectroscopy in ALS and noted that elevated choline in some contexts may reflect membrane turnover and neuroinflammation rather than nutritional adequacy. It also cited Latif and Kang (2022), who found protective effects of choline against cytokine-induced cytotoxicity in motor neuron-like cell lines. There is also mechanistic interest in NRF2-related antioxidant and anti-inflammatory pathways, although those data are further from a direct ALS treatment conclusion (Kalra, 2019; Latif & Kang, 2022; Jiménez-Villegas et al., 2021).

That mixed picture is worth sitting with. Choline can appear in the literature as part of a protective response, part of altered membrane turnover, part of metabolomic dysregulation, or part of inflammatory signalling. It is not one simple marker with one simple meaning.

Glutamate toxicity adds another layer

Another recurring theme in ALS is glutamate excitotoxicity, which is the damage that can occur when excitatory signalling becomes excessive or poorly controlled. If you think of glutamate as one of the nervous system’s “go” signals, excitotoxicity is what happens when that signal becomes too loud for too long (Herrando-Grabulosa et al., 2021; Donatti et al., 2020).

Kirstie Lawton’s (PhD) scoping review noted that raised glutamate in ALS has been linked to reduced uptake and increased astrocytic release, and that cytidine diphosphate-choline (CDP-choline) has been reported to increase excitatory amino acid transporter 2 (EAAT2) expression and enhance glutamate uptake into astrocytes in preclinical work (Knippenberg et al., 2013). That is an interesting mechanistic signal, but the same paper also offers an important note of caution: CDP-choline was not protective i(SOD1-G93A)mouse model of ALS. So while the mechanism looks biologically plausible, it did not translate into a clear disease-modifying effect in that model (Knippenberg et al., 2013).

That negative result matters. It keeps this discussion honest.

What does the human evidence actually look like?

This is the point where a lot of mechanistic stories either grow up or fall apart.

In humans, the evidence is not yet clean. Atassi et al. (2017) did not find significant differences in choline-containing components between ALS participants and controls in 7T magnetic resonance spectroscopy, although other metabolite patterns were informative. Bjornevik et al. (2019) found evidence of broad metabolic dysregulation years before disease onset, including positive associations for two phosphatidylcholines and a sphingomyelin, but these did not remain significant after multiple-comparison adjustment and the overall metabolomic profile did not reliably distinguish future ALS cases from controls. More recently, Gautam et al. (2025) identified choline among dysregulated metabolites in an Indian ALS cohort, but this was a pilot case-control study and still far from clinical application (Atassi et al., 2017; Bjornevik et al., 2019; Gautam et al., 2025).

So where does that leave us?

In a place that is less dramatic but more useful. Choline looks biologically relevant. It appears close to several mechanisms implicated in ALS. It may influence signalling, membrane integrity, calcium control, oxidative stress, inflammatory tone, and metabolomic patterns. But the clinical story is still emerging, and none of this justifies a simplistic “ALS is a choline deficiency disease” narrative.

The real meaning of all this

The strongest reading of the evidence is not that choline is the missing answer to ALS.

It is that ALS exposes how much motor neurones depend on membrane quality, stress signalling, calcium control, mitochondrial competence, and carefully managed communication. Choline happens to sit near all of those systems. That makes it scientifically important, even if it is not yet clinically decisive (Burns et al., 2025; Herrando-Grabulosa et al., 2021; Scoping review, 2026).

And that is probably the most honest reason to keep looking at it.

Not because the case is closed.

But because the biology keeps pointing in the same direction.

In Part 3 of this series, we’ll leave the microscope behind and move into the practical questions people actually want answered. What foods provide meaningful amounts of choline? Can you test choline status in any useful way? What about phosphatidylcholine, citicoline, alpha-GPC, and the question of Trimethylamine N-oxide (TMAO)? And where should real caution sit when a mechanistic story starts turning into supplement marketing?

Support for MND, ALS and PLS at You Nutrition Clinic

At You Nutrition Clinic, Kirstie leads our MND, ALS and PLS team alongside Kerry (RNTP), Deborah (RD) and Rachael (RN). We support people at every stage of the journey with an approach that is empathetic, thorough and evidence-based.

Although there is no cure for MND or ALS, there is often still meaningful scope to support symptoms, nutritional status and quality of life. Our work begins with a full health history and a detailed review of possible symptom drivers, before building a personalised plan focused on diet, gut health, lifestyle and wider functional support. Where appropriate, we may also use testing to explore nutrient status, metabolic function, immune markers, environmental exposures and mitochondrial health.

If you would like personalised support for MND, ALS or PLS, get in touch with You Nutrition Clinic to learn more at admin@younutritionclinic.com for a free initial chat.

🧩 Connect with us

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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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