Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord.
Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord.
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DOI：
10.1038/srep42292
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Crouch PJ
中科院分区：
文献类型：
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作者：
Hilton JB;Mercer SW;Lim NK;Faux NG;Buncic G;Beckman JS;Roberts BR;Donnelly PS;White AR;Crouch PJ
突变型Cu/ zn -超氧化物歧化酶（SOD1）的普遍表达选择性地影响中枢神经系统（CNS）的运动神经元，导致成人发病的退行性疾病肌萎缩侧索硬化症（ALS）。无处不在的SOD1突变表达对中枢神经系统的特异性影响在该疾病的转基因小鼠模型中得到了概括。在这里，我们介绍了金属复合物CuII（atsm）在混合遗传背景下表达SOD1G93A的小鼠中测试治疗效果的结果。口服CuII（atsm）延缓了神经症状的发作，改善了运动能力，延长了总生存期。虽然SOD1G93A小鼠的als样表型是由突变体SOD1的表达引起的，但我们发现CuII（atsm）治疗动物的表型改善涉及到疾病影响脊髓中成熟突变体SOD1蛋白的增加，其中铜和SOD1活性的增加也很明显。与脊髓中的这些作用相反，用CuII（atsm）治疗对肝脏中SOD1突变蛋白水平及其活性均无影响，表明该药物对中枢神经系统选择性SOD1有反应。这些数据为CuII（atsm）作为ALS的治疗方案提供了支持，也为SOD1突变体的中枢神经系统选择性作用提供了见解。
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.