Kabashi Edor, Valdmanis Paul N, Dion Patrick, Rouleau Guy A
Centre for Excellence in Neuromics, University of Montreal, the Centre Hospitalier de l'Université de Montreal and Ste-Justine Hospital, Montreal, Quebec, Canada.
Ann Neurol. 2007 Dec;62(6):553-9. doi: 10.1002/ana.21319.
The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.
1993年，超氧化物歧化酶-1（SOD1）突变被确定为导致10%至20%的家族性肌萎缩侧索硬化症病例的病因，而家族性肌萎缩侧索硬化症病例占所有肌萎缩侧索硬化症（ALS）病例的1%至2%，这引发了大量关于SOD1介导毒性机制的研究。最近的实验表明，野生型SOD1的氧化会导致其错误折叠，使其获得许多与突变型SOD1相同的毒性特性。对氧化/错误折叠的SOD1的体外研究以及对错误折叠的SOD1的体内研究表明，这些蛋白质种类对运动神经元具有选择性毒性，这表明即使在不携带SOD1突变的个体中，氧化/错误折叠的SOD1也可能导致ALS。也有报道称，神经胶质细胞将氧化/错误折叠的突变型SOD1分泌到细胞外环境中，在那里它可以触发运动神经元的选择性死亡，这为突变型SOD1毒性的非细胞自主性本质以及疾病一旦出现首发症状就迅速进展提供了一种可能的解释。因此，考虑到散发性（SALS）和家族性ALS（FALS）病例在临床上难以区分，突变型SOD1的毒性特性与氧化/错误折叠的野生型SOD1（wtSOD1）相似，并且分泌的/细胞外错误折叠的SOD1对运动神经元具有选择性毒性，我们提出氧化/错误折叠的SOD1是大多数经典ALS形式发病的原因，应该成为ALS治疗设计的主要靶点。
