Tham khảo tài liệu 'amyotrophic lateral sclerosis part 9', khoa học tự nhiên, công nghệ sinh học phục vụ nhu cầu học tập, nghiên cứu và làm việc hiệu quả | 302 Amyotrophic Lateral Sclerosis accessibility of substrates to Cu in the protein to generate reactive oxygen or nitrogen species. There is direct evidence that mutant SOD1 can promote abnormal pro-oxidant reactions cooperated with Cu. Mutant SOD1 unlike wild type SOD1 has a potential to generate hydroxyl radicals Wiedau-Pazos et al. 1996 Yim et al. 1996 or peroxynitrite Estevez et al. 1999 by Cu-dependent reaction in vitro which can be inhibited by Cu chelators in cultured cells Ghadge et al. 1997 . Cu-mediated toxicity in mutant SOD1 is also reinforced with the reports that decreasing intracellular Cu by treatment with Cu chelators or genetic reduction of Cu uptake alleviates ALS phenotype in mutant SOD1 transgenic mice Hottinger et al. 1997 Kiaei et al. 2004 Nagano et al. 2003 Tokuda et al. 2008 . Moreover metallothioneins which bind Cu to prevent it from being pro-oxidant are increased in the spinal cord of mutant SOD1 mice to attenuate the disease expression Hashimoto et al. 2011 Nagano et al. 2001 Tokuda et al. 2007 . These facts suggest that Cu-mediated oxidative chemistry underlies the pathogenesis of familial ALS linked to mutations of SOD1 gene. On the other hand the phenotype of mutant SOD1 mice was not rescued by genetic removal of the Cu chaperone for SOD1 CCS which incorporates Cu into the buried active site of SOD1 Subramaniam et al. 2002 . Furthermore mutant SOD1 still induces the disease in transgenic mice even when the active copper-binding site is totally disrupted by multiple mutations Wang et al. 2003 . These findings had been taken as evidence against the hypothesis of aberrant Cu chemistry in the toxicity of mutant SOD1. However the theory implicating Cu toxicity cannot be excluded since ectopic binding of Cu away from the active site for example could contribute to the pathogenesis. In fact H46R mutant SOD1 which disrupts Cu binding at the active site still has the ectopic binding of Cu Liu et al. 2000 . 3. Increased affinity for Cu in .
