Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

Eiichi Tokuda, Shunsuke Watanabe, Eriko Okawa, Shin ichi Ono

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1<sup>G93A</sup>). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1<sup>G93A</sup> mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1<sup>G93A</sup> aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1<sup>G93A</sup> mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

Original languageEnglish
Pages (from-to)461-476
Number of pages16
JournalNeurotherapeutics
Volume12
Issue number2
DOIs
Publication statusPublished - 2015 Apr 1
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis
  • Copper dyshomeostasis
  • Dexamethasone
  • Metallothioneins
  • Superoxide dismutase-1

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Pharmacology

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