Tokuda Eiichi, Ono Shin-ichi, Ishige Kumiko, Watanabe Shunsuke, Okawa Eriko, Ito Yoshihisa, Suzuki Takashi
Research Unit of Clinical Pharmacy, College of Pharmacy, Nihon University, Chiba, Japan.
Exp Neurol. 2008 Sep;213(1):122-8. doi: 10.1016/j.expneurol.2008.05.011. Epub 2008 May 23.
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 (SOD1(G93A)). 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 SOD1(G93A). 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.
铜/锌超氧化物歧化酶（SOD1）突变会导致一种家族性肌萎缩侧索硬化症（ALS）。家族性ALS的发病机制可能与突变型SOD1中半胱氨酸残基引起的异常铜化学性质有关。四硫代钼酸铵（TTM）是一种铜螯合剂，能够从硫醇铜簇（如SOD1）中去除铜离子。我们发现TTM在家族性ALS小鼠模型（SOD1(G93A)）中具有治疗作用。TTM治疗显著延迟了疾病发作，减缓了疾病进展，并使生存期延长了约20%、42%和25%。TTM还有效降低了脊髓铜离子水平并抑制了脂质过氧化，同时显著抑制了SOD1(G93A)中SOD1的酶活性。这些结果支持了这样的假设，即通过半胱氨酸残基产生的异常铜化学性质在突变型SOD1毒性中起关键作用，并且TTM可能是治疗具有SOD1突变的家族性ALS的一种有前景的疗法。
