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

40 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
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Disease Progression
Copper
Cysteine
Ions
tetrathiomolybdate
Lipid Peroxidation
Superoxide Dismutase
Zinc
Mutation
Amyotrophic lateral sclerosis 1
Therapeutics
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis. / Tokuda, Eiichi; Ono, Shin ichi; Ishige, Kumiko; Watanabe, Shunsuke; Okawa, Eriko; Ito, Yoshihisa; Suzuki, Takashi.

In: Experimental Neurology, Vol. 213, No. 1, 09.2008, p. 122-128.

Research output: Contribution to journalArticle

Tokuda, Eiichi ; Ono, Shin ichi ; Ishige, Kumiko ; Watanabe, Shunsuke ; Okawa, Eriko ; Ito, Yoshihisa ; Suzuki, Takashi. / Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis. In: Experimental Neurology. 2008 ; Vol. 213, No. 1. pp. 122-128.
@article{707c762a273a4635b31104924943cab7,
title = "Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis",
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.",
keywords = "Ammonium tetrathiomolybdate, Amyotrophic lateral sclerosis, Copper, Copper/zinc superoxide dismutase, Cysteine residue",
author = "Eiichi Tokuda and Ono, {Shin ichi} and Kumiko Ishige and Shunsuke Watanabe and Eriko Okawa and Yoshihisa Ito and Takashi Suzuki",
year = "2008",
month = "9",
doi = "10.1016/j.expneurol.2008.05.011",
language = "English",
volume = "213",
pages = "122--128",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis

AU - Tokuda, Eiichi

AU - Ono, Shin ichi

AU - Ishige, Kumiko

AU - Watanabe, Shunsuke

AU - Okawa, Eriko

AU - Ito, Yoshihisa

AU - Suzuki, Takashi

PY - 2008/9

Y1 - 2008/9

N2 - 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.

AB - 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.

KW - Ammonium tetrathiomolybdate

KW - Amyotrophic lateral sclerosis

KW - Copper

KW - Copper/zinc superoxide dismutase

KW - Cysteine residue

UR - http://www.scopus.com/inward/record.url?scp=49349115593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49349115593&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2008.05.011

DO - 10.1016/j.expneurol.2008.05.011

M3 - Article

C2 - 18617166

AN - SCOPUS:49349115593

VL - 213

SP - 122

EP - 128

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -