Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis

Eiichi Tokuda, Shin ichi Ono, Kumiko Ishige, Shunsuke Watanabe, Eriko Okawa, Yoshihisa Ito, Takashi Suzuki

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Mutations in copper/zinc superoxide dismutase (SOD1) cause a form of familial amyotrophic lateral sclerosis (ALS). The pathogenesis of familial ALS may be associated with aberrant copper chemistry through a cysteine residue in mutant SOD1. Ammonium tetrathiomolybdate (TTM) is a copper-chelating drug that is capable of removing a copper ion from copper-thiolate clusters, such as SOD1. We found that TTM exerted therapeutic benefits in a mouse model of familial ALS (SOD1G93A). TTM treatment significantly delayed disease onset, slowed disease progression and prolonged survival by approximately 20%, 42% and 25%, respectively. TTM also effectively depressed the spinal copper ion level and inhibited lipid peroxidation, with a significant suppression of SOD1 enzymatic activity in SOD1G93A. These results support the hypothesis that aberrant copper chemistry through a cysteine residue plays a critical role in mutant SOD1 toxicity and that TTM may be a promising therapy for familial ALS with SOD1 mutants.

Original languageEnglish
Pages (from-to)122-128
Number of pages7
JournalExperimental Neurology
Volume213
Issue number1
DOIs
Publication statusPublished - 2008 Sep 1

Keywords

  • Ammonium tetrathiomolybdate
  • Amyotrophic lateral sclerosis
  • Copper
  • Copper/zinc superoxide dismutase
  • Cysteine residue

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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