Jonsson P Andreas, Graffmo Karin S, Brännström Thomas, Nilsson Peter, Andersen Peter M, Marklund Stefan L
Department of Medical Biosciences, Umeå University Hospital, SE-901 85 Umeå, Sweden.
J Neuropathol Exp Neurol. 2006 Dec;65(12):1126-36. doi: 10.1097/01.jnen.0000248545.36046.3c.
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.
突变型人类铜锌超氧化物歧化酶（hSOD1）可导致肌萎缩侧索硬化症（ALS）。最常见的突变是野生型样的D90A，为探究其特性，构建了转基因小鼠并与表达野生型hSOD1的小鼠进行比较。D90A hSOD1在小鼠体内以及变性条件下的体外稳定性几乎与野生型人类酶相当。它似乎比其他测试突变体毒性更小，但转基因插入纯合的小鼠却患上了致命的运动神经元疾病。在这些小鼠中，疾病进展缓慢，并且存在膀胱功能障碍，类似于在D90A突变纯合的人类ALS病例中所发现的情况。纯合D90A小鼠在脊髓中积累了抗去污剂的hSOD1聚集体，并且在腹角可见大量hSOD1包涵体和空泡。以相当速率表达野生型hSOD1的小鼠表现出类似的病理变化，但程度较轻且出现较晚。半合子D90A小鼠的变化甚至更轻微。在600天时，野生型hSOD1转基因小鼠比半合子D90A小鼠损失了更多的腹角神经元（38%对31%，p<0.01）。因此，野生型hSOD1在脊髓中显示出显著的神经毒性，其毒性小于D90A突变酶，但大于其一半。
