Disrupted Balance of Copper Variants, Not Copper Levels, Involved in ALS

The balance between copper isotopes (variants) – but not copper levels – is disrupted in patients with amyotrophic lateral sclerosis (ALS), according to a recent study.

Copper isotope composition potentially may be used as a biomarker of ALS, distinguishing it from other neurodegenerative diseases, such as Alzheimer’s.

The study, “Isotopic Evidence for Disrupted Copper Metabolism in Amyotrophic Lateral Sclerosis,” was published in the journal iScience.

Several studies have shown that the progression of neurodegenerative diseases, including ALS, is associated with the production of reactive oxygen species, which are oxygen-associated molecules that contribute to oxidative stress and cell damage.

The presence of free, redox-active metals like copper (Cu) promote the production of these potentially damaging molecules. Copper is a micronutrient that needs other molecules to be absorbed and transported into the central nervous system (brain and spinal cord), where it is involved in various functions.

Increasing evidence from animal models and patients has suggested that dysregulation of the balance of several metals, such as copper, iron, and zinc in the cerebrospinal fluid (the fluid around the brain and the spinal cord) and brain is associated with ALS.

However, the findings regarding the usefulness of metal concentrations to diagnose and study ALS are inconsistent.

The ratio between copper variants (65Cu/63Cu) or their composition may be a more accurate and valuable measure to assess specific changes in neurodegenerative diseases.

It is measured with a greater precision than concentrations, and 65Cu values have been shown to significantly differ between women and men, with age, and in disease, such as cancer and Wilson disease (a neurodegenerative disorder associated with copper metabolism).

Researchers in France evaluated the potential use of the concentration of 12 elements (including copper and zinc) and copper and zinc variant compositions in the cerebrospinal fluid to distinguish and study ALS.

They analyzed the cerebrospinal fluid of 31 ALS patients, 14 people with Alzheimer’s disease, and 11 age-matched healthy people.

While ALS patients showed significant lower iron and manganese (Mn) concentrations and higher rubidium (Rb) compared with the other two groups, copper and zinc concentrations were not significantly altered in these patients.

These results suggested that “metal concentrations weakly discriminate patients with ALS from the two other groups,” the researchers wrote.

In turn, patients with ALS had significantly more 65Cu than healthy people and Alzheimer’s patients, suggesting the involvement of copper in ALS and its potential use to diagnose or distinguish ALS from other neurodegenerative diseases.

The researchers noted that additional studies are needed to confirm their results and their hypothesis, and that isotopic analysis may be a potential tool to understand the underlying molecular mechanisms of ALS.

Also, people with Alzheimer’s showed a slight difference in zinc isotopic compositions when compared with healthy people, which the team noted may bring additional knowledge regarding the dysregulation of zinc metabolism in Alzheimer’s disease.