The Copper Chelator d‐Penicillamine Delays Onset of Disease and Extends Survival in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis
The Copper Chelator d‐Penicillamine Delays Onset of Disease and Extends Survival in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis
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铜螯合剂 d-青霉胺可延迟家族性肌萎缩侧索硬化症转基因小鼠模型的发病并延长其生存期
DOI：
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发表时间：
1997
影响因子：
3.4
通讯作者：
P. Aebischer
中科院分区：
文献类型：
--
作者：
A. Hottinger;E. Fine;M. Gurney;A. Zurn;P. Aebischer
肌萎缩侧索硬化症家族病例的一个亚群被认为与编码铜/锌超氧化物歧化酶(SOD1)的基因突变有关。有体外证据表明，某些SOD1突变体，除了它们正常的歧化功能外，还表现出该酶作为过氧化物酶的能力增强。该反应对铜络合剂的抑制很敏感。为了在体内验证这一假说，我们给家族性肌萎缩侧索硬化症转基因小鼠模型注射了铜螯合剂d-青霉胺，该模型过度表达突变形式的人SOD1。我们证明，口服d-青霉胺能够延缓疾病的发生，延长这些小鼠的生存时间。组织学研究还显示，在d-青霉胺处理的转基因小鼠中，面部运动神经元的损失减少，证实了这些动物中疾病演变的缓慢。这些结果表明，铜络合剂可能有益于与SOD1基因突变相关的家族性肌萎缩侧索硬化症患者。
A subpopulation of familial cases of amyotrophic lateral sclerosis has been linked to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). There is in vitro evidence that certain SOD1 mutants, in addition to their normal dismutation function, show increased ability of the enzyme to act as a peroxidase. This reaction is sensitive to inhibition by copper chelators. To test this hypothesis in vivo, we administered the copper chelator d‐penicillamine to a transgenic mouse model of familial amyotrophic lateral sclerosis overexpressing a mutated form of human SOD1. We demonstrate that oral administration of d‐penicillamine is able to delay the onset of the disease and extend the survival of these mice. Histological studies also showed a decreased loss of facial motor neurons in d‐penicillamine‐treated transgenic mice, corroborating the slower evolution of the disease in these animals. These results suggest that copper chelators may benefit patients with familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene.
DOI：
10.1073/pnas.91.17.8292
发表时间：
1994-08-16
影响因子：
11.1
作者：
BORCHELT, DR;LEE, MK;CLEVELAND, DW
通讯作者：
CLEVELAND, DW