Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1
Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1
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DOI：
10.1097/01.jnen.0000248545.36046.3c
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发表时间：
2006-12-01
影响因子：
3.2
通讯作者：
Marklund, Stefan L.
中科院分区：
文献类型：
--
作者：
Jonsson, P. Andreas;Graffmo, Karin S.;Marklund, Stefan L.
突变的人铜锌超氧化物歧化酶(HSOD1s)可引起肌萎缩侧索硬化症(ALS)。最常见的突变是类似野生型的D90A，为了探索其特性，我们产生了转基因小鼠，并与表达野生型hSOD1的小鼠进行了比较。D90A hSOD1在小鼠体内和体外变性条件下几乎与野生型人类酶一样稳定。它的毒性似乎比其他测试的突变体要小，但转基因插入纯合的小鼠患上了一种致命的运动神经元疾病。在这些小鼠中，疾病进展缓慢，并有类似于在D90A突变纯合子的人类ALS病例中发现的膀胱障碍。纯合子D90A小鼠在脊髓中聚集了耐洗涤剂的hSOD1聚集体，腹角可见丰富的hSOD1包涵体和空泡。以类似的速度表达野生型hSOD1的小鼠表现出类似的病理变化，但越来越少。半合子D90A小鼠表现出更轻微的变化。600天后，野生型hSOD1转基因小鼠比半合子D90A小鼠失去了更多的腹角神经元(38%比31%p<；0.01)。因此，野生型hSOD1在脊髓中显示出显著的神经毒性，不到D90A突变酶的一半，但不到D90A突变酶的一半。
Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The most common mutation is the wild type-like D90A and to explore its properties, transgenic mice were generated and compared with mice expressing wild-type hSOD1. D90A hSOD1 was both in vivo in mice and in vitro under denaturing conditions nearly as stable as the wild-type human enzyme. It appeared less toxic than other tested mutants, but mice homozygous for the transgene insertion developed a fatal motor neuron disease. In these mice, the disease progression was slow and there were bladder disturbances similar to what is found in human ALS cases homozygous for the D90A mutation. The homozygous D90A mice accumulated detergent-resistant hSOD1 aggregates in spinal cords, and abundant hSOD1 inclusions and vacuoles were seen in the ventral horns. Mice expressing wild-type hSOD1 at a comparable rate showed similar pathologic changes but less and later. Hemizygous D90A mice showed even milder alterations. At 600 days, the wild-type hSOD1 transgenic mice had lost more ventral horn neurons than hemizygous D90A mice (38% vs 31% p < 0.01). Thus, wild-type hSOD1 shows a significant neurotoxicity in the spinal cord, that is less than equal but more than half as large as that of D90A mutant enzyme.