Department of Chemistry, Laboratory for Mechanistic Chemistry of Biomolecules, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama, Kanagawa, 223-8522, Japan.
Present address: Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
Transl Neurodegener. 2020 Aug 19;9(1):33. doi: 10.1186/s40035-020-00209-y.
Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.
肌萎缩侧索硬化症（ALS）的特征是成年起病的上下运动神经元进行性退化。越来越多的基因被发现与 ALS 有关；在这些基因中，第一个被鉴定的基因 SOD1 编码铜/锌-超氧化物歧化酶蛋白（SOD1），被认为是 ALS 发病机制研究的金标准。突变型 SOD1 引起的 ALS 中，受影响的脊髓运动神经元中异常聚集的错误折叠 SOD1 已被确立为病理性特征（SOD1-ALS）。尽管如此，野生型 SOD1 的参与在没有 SOD1 突变的 ALS （非 SOD1 ALS）的病理学中仍然存在很大争议，占总 ALS 病例的 90%以上。体外研究表明野生型和突变型 SOD1 蛋白的翻译后控制错误折叠和聚集；因此，SOD1 蛋白不仅是 SOD1-ALS 的治疗靶点，也是更常见的非 SOD1 ALS 的治疗靶点。为了寻找体内野生型 SOD1 错误折叠和聚集的证据，我们回顾了使用小鼠模型和患者的病理学研究，并总结了野生型 SOD1 可能参与非 SOD1 ALS 以及 SOD1-ALS 的论据。
