Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis

Eiichi Tokuda, Eriko Okawa, Shin Ichi Ono

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Mutations in copper/zinc superoxide dismutase (SOD1) are responsible for 20% of familial amyotrophic lateral sclerosis through a gain-of-toxic function. We have recently shown that ammonium tetrathiomolybdate, an intracellular copper-chelating reagent, has an excellent therapeutic benefit in a mouse model for amyotrophic lateral sclerosis. This finding suggests that mutant SOD1 might disrupt intracellular copper homeostasis. In this study, we investigated the effects of mutant SOD1 on the components of the copper trafficking pathway, which regulate intracellular copper homeostasis. We found that mutant, but not wild-type, SOD1 shifts intracellular copper homeostasis toward copper accumulation in the spinal cord during disease progression: copper influx increases, copper chaperones are up-regulated, and copper efflux decreases. This dysregulation was observed within spinal motor neurons and was proportionally associated with an age-dependent increase in spinal copper ion levels. We also found that a subset of the copper trafficking pathway constituents co-aggregated with mutant SOD1. These results indicate that the nature of mutant SOD1 toxicity might involve the dysregulation of the copper trafficking pathway, resulting in the disruption of intracellular copper homeostasis.

Original languageEnglish
Pages (from-to)181-191
Number of pages11
JournalJournal of Neurochemistry
Volume111
Issue number1
DOIs
Publication statusPublished - 2009 Oct
Externally publishedYes

Fingerprint

Superoxide Dismutase
Zinc
Copper
Homeostasis
Amyotrophic lateral sclerosis 1
Spinal Cord Diseases
Poisons
Amyotrophic Lateral Sclerosis
Motor Neurons
Chelation
Neurons
Toxicity
Disease Progression
Ions

Keywords

  • Amyotrophic lateral sclerosis
  • Copper trafficking pathway
  • Copper/zinc superoxide dismutase
  • Glial cell
  • Intracellular copper homeostasis
  • Motor neuron

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis. / Tokuda, Eiichi; Okawa, Eriko; Ono, Shin Ichi.

In: Journal of Neurochemistry, Vol. 111, No. 1, 10.2009, p. 181-191.

Research output: Contribution to journalArticle

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