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 language | English |
|---|---|
| Pages (from-to) | 122-128 |
| Number of pages | 7 |
| Journal | Experimental Neurology |
| Volume | 213 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2008 Sep |
| Externally published | Yes |
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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 journal › Article
}
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
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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 -