Choi Inhee, Yang Young In, Song Hyeon Don, Lee Jeong Seon, Kang Taewook, Sung Jung-Joon, Yi Jongheop
School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 151-742, Korea.
Biochim Biophys Acta. 2011 Jan;1812(1):41-8. doi: 10.1016/j.bbadis.2010.09.003. Epub 2010 Sep 15.
Cu/Zn-superoxide dismutase (SOD1) is present in the cytosol, nucleus, peroxisomes and mitochondrial intermembrane space of human cells. More than 114 variants of human SOD1 have been linked to familial amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease. Although the ultimate mechanisms underlying SOD1-mediated cytotoxicity are largely unknown, SOD1 aggregates have been strongly implicated as a common feature in ALS. This study examined the mechanism for the formation of SOD1 aggregates in vitro as well as the nature of its cytotoxicity. The aggregation propensity of SOD1 species was investigated using techniques ranging from circular dichroism spectroscopy to fluorescence dye binding methods, as well as electron microscopic imaging. The aggregation of SOD1 appears to be related to its structural instability. The demetallated (apo)-SOD1 and aggregated SOD1 species, with structurally disordered regions, readily undergo aggregation in the presence of lipid molecules, whereas metallated (holo)-SOD1 does not. The majority of aggregated SOD1s that are induced by lipid molecules have an amorphous morphology and exhibit significant cytotoxicity. The lipid binding propensity of SOD1 was found to be closely related to the changes in surface hydrophobicity of the proteins, even at very low levels, which induced further binding and assembly with lipid molecules. These findings suggest that lipid molecules induce SOD1 aggregation under physiological conditions and exert cytotoxicity, and might provide a possible mechanism for the pathogenesis of ALS.
铜锌超氧化物歧化酶（SOD1）存在于人类细胞的胞质溶胶、细胞核、过氧化物酶体和线粒体内膜间隙中。超过114种人类SOD1变体与家族性肌萎缩侧索硬化症（ALS，也称为卢伽雷氏病）有关。尽管SOD1介导的细胞毒性的最终机制在很大程度上尚不清楚，但SOD1聚集体已被强烈认为是ALS的一个共同特征。本研究探讨了SOD1聚集体在体外形成的机制及其细胞毒性的本质。使用从圆二色光谱到荧光染料结合方法以及电子显微镜成像等技术研究了SOD1物种的聚集倾向。SOD1的聚集似乎与其结构不稳定性有关。去金属化（脱辅基）的SOD1和具有结构无序区域的聚集SOD1物种在脂质分子存在下容易发生聚集，而金属化（全酶）的SOD1则不会。大多数由脂质分子诱导的聚集SOD1具有无定形形态并表现出显著的细胞毒性。发现SOD1的脂质结合倾向与蛋白质表面疏水性的变化密切相关，即使在非常低的水平下，这种变化也会诱导与脂质分子的进一步结合和组装。这些发现表明，脂质分子在生理条件下诱导SOD1聚集并发挥细胞毒性，这可能为ALS的发病机制提供一种可能的解释。
