Department of Biochemistry and Biophysics, 120 Mason Farm Road, CB# 7260, University of North Carolina , Chapel Hill, North Carolina, United States 27599.
Biochemistry. 2014 Apr 15;53(14):2423-32. doi: 10.1021/bi500158w. Epub 2014 Apr 2.
Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS.
可溶性错误折叠的 Cu/Zn 超氧化物歧化酶（SOD1）与肌萎缩侧索硬化症（ALS）中的运动神经元死亡有关；然而，SOD1 错误折叠和聚集形成的各种非天然物种的相对毒性尚不清楚。在这里，我们证明 SOD1 聚集的早期阶段涉及可溶性寡聚物的形成，这些寡聚物含有针对与疾病相关的错误折叠 SOD1 的表位；该表位被 C4F6 抗体识别，被提议作为毒性物种的标志物。氧化性细胞环境可能会加剧潜在毒性寡聚物的形成，这一点可以通过谷胱甘肽的氧化修饰存在于 Cys-111 时增加寡聚物化倾向和 C4F6 反应性来证明。这些发现表明，可溶性非天然 SOD1 寡聚物与在 ALS 患者中发现的致病性错误折叠物种具有结构相似性，而不是类似天然的二聚体或单体，因此代表 ALS 中的潜在细胞毒性剂和治疗靶点。
