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Lovejoy DB, Guillemin GJ. The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis. Front Aging Neurosci. 2014;6:173doi: 10.3389/fnagi.2014.00173.
Lovejoy, D. B., & Guillemin, G. J. (2014). The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis. Frontiers in aging neuroscience, 6173. https://doi.org/10.3389/fnagi.2014.00173
Lovejoy, David B, and Guillemin, Gilles J. "The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis." Frontiers in aging neuroscience vol. 6 (2014): 173. doi: https://doi.org/10.3389/fnagi.2014.00173
Lovejoy DB, Guillemin GJ. The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis. Front Aging Neurosci. 2014 Jul 23;6:173. doi: 10.3389/fnagi.2014.00173. eCollection 2014. PMID: 25100994; PMCID: PMC4107949.
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Front Aging Neurosci. 2014 Jul 23;6:173. doi: 10.3389/fnagi.2014.00173. eCollection 2014.

The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis.

Frontiers in aging neuroscience

David B Lovejoy, Gilles J Guillemin

Affiliations

  1. Australian School of Advanced Medicine, Macquarie University , Sydney, NSW , Australia.

PMID: 25100994 PMCID: PMC4107949 DOI: 10.3389/fnagi.2014.00173

Abstract

Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons, and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER) stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy.

Keywords: ER stress; amyotrophic lateral sclerosis; copper; iron; neurodegeneration; transition metals

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