Lipid molecules induce the cytotoxic aggregation of Cu/Zn superoxide dismutase with structurally disordered regions

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1812

Article

Choi, Inhee¹  Yang, Young In¹  Song, Hyeon Don¹  Lee, Jeong Seon^2,3  Kang, Taewook⁴  Sung, Jung-Joon^2,3  Yi, Jongheop¹ 

[1] Seoul Natl Univ, Inst Chem Proc, Sch Chem & Biol Engn, Seoul 151742, South Korea

[2] Dept Neurol, Seoul 110744, South Korea

[3] Seoul Natl Univ, Coll Med, Seoul 110744, South Korea

[4] Sogang Univ, Dept Chem & Biomol Engn, Seoul 121742, South Korea

关键词: Amyotrophic lateral sclerosis;    Aggregation;    Cu/Zn-superoxide dismutase;    Cytotoxicity;    Lipid molecules;    Lou Gehrig's disease;   

DOI  :  10.1016/j.bbadis.2010.09.003

来源: Elsevier

【 摘 要 】

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. (c) 2010 Elsevier B.V. All rights reserved.

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