Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis |
| |
Authors: | Tokuda Eiichi Ono Shin-ichi Ishige Kumiko Watanabe Shunsuke Okawa Eriko Ito Yoshihisa Suzuki Takashi |
| |
Institution: | aResearch Unit of Clinical Pharmacy, College of Pharmacy, Nihon University, Chiba, Japan;bDivision of Neurology, Akiru Municipal Medical Center, Tokyo, Japan;cResearch Unit of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan;dDepartment of Pediatrics, Nihon University School of Medicine, Tokyo, Japan |
| |
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 |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|