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  • Review Article
  • Published:

Iron in multiple sclerosis: roles in neurodegeneration and repair

Key Points

  • Multiple sclerosis (MS) involves profound destruction of oligodendrocytes and myelin

  • MRI and histological studies suggest that iron levels are dysregulated in MS: iron accumulates in grey matter and is depleted in normal-appearing white matter

  • Iron accumulation promotes cytotoxicity through a variety of mechanisms, including chemical reactions leading to oxidative stress, increased proinflammatory cytokine levels, glutamate toxicity, and impaired DNA repair

  • Iron is a cofactor for a variety of enzymes involved in maintaining the health of oligodendrocytes and myelin, and may be a crucial component of remyelination

  • Treatments for iron excess in MS must address not only the increased iron levels within grey matter, but also the requirement for iron in remyelination and repair

  • The extracellular matrix, a key regulator of remyelination, may also modulate iron availability

Abstract

MRI and histological studies have shown global alterations in iron levels in the brains of patients with multiple sclerosis (MS), including increases in the iron stored by macrophages and microglia. Excessive free iron can be toxic, and accumulation of iron in MS has generally been thought to be detrimental. However, iron maintains the integrity of oligodendrocytes and myelin, and facilitates their regeneration following injury. The extracellular matrix, a key regulator of remyelination, might also modulate iron levels. This Review highlights key histological and MRI studies that have investigated changes in iron distribution associated with MS. Potential sources of iron, as well as iron regulatory proteins and the detrimental roles of excessive iron within the CNS, are also discussed, with emphasis on the importance of iron within cells for oxidative metabolism, proliferation and differentiation of oligodendrocytes, and myelination. In light of the beneficial and detrimental properties of iron within the CNS, we present considerations for treatments that target iron in MS. Such treatments must balance trophic and toxic properties of iron, by providing sufficient iron levels for remyelination and repair while avoiding excesses that might overwhelm homeostatic mechanisms and contribute to damage.

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Figure 1: Iron deposits in MS revealed through imaging and histopathology.
Figure 2: Iron homeostasis and metabolism.
Figure 3: The role of iron-containing enzymes in remyelination.
Figure 4: Balancing the toxic and trophic properties of iron.

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Acknowledgements

The authors' studies have been funded by the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada, and the Alberta Innovates–Health Solutions CRIO Team programme.

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All authors researched data for the article, made substantial contributions to discussions of the content, and wrote and edited the manuscript before submission.

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Correspondence to V. Wee Yong.

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Stephenson, E., Nathoo, N., Mahjoub, Y. et al. Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol 10, 459–468 (2014). https://doi.org/10.1038/nrneurol.2014.118

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