Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis

TL;DR

This study finds that lower levels of a protein called metallothionein-3 are linked to copper imbalance in the spinal cords of people with ALS and MS.

Contribution

The study reveals a common link between reduced metallothionein-3 and copper dysregulation in both ALS and MS.

Findings

ALS and MS spinal cords show significantly decreased metallothionein-3 levels compared to controls.

Reduced metallothionein-3 correlates with altered copper levels and binding in both diseases.

The findings support copper dysregulation as a shared feature of ALS and MS.

Abstract

Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are devastating adult-onset neurological diseases with distinct pathological manifestations. Although growing evidence implicates copper dysregulation in both diseases, our understanding of this connection remains incomplete. In this study, we investigated metallothionein-3 (MT3), which is a key regulator of copper metabolism in the central nervous system (CNS), and its relationship to copper in the ALS and MS spinal cord. Using combined quantitative mass spectrometry approaches and immunohistochemical observations, we found a significant decrease in ALS and MS spinal cord MT3 levels compared to controls. This was correlated with levels of copper and MT3-copper binding, highlighting a strong relationship between copper and MT3 levels. These findings demonstrate decreased MT3 expression alongside copper as a common feature of ALS and MS supporting previously reported evidence for copper dysregulation in these diseases.

The online version contains supplementary material available at 10.1038/s41598-025-31283-9.

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