Interactions between superoxide dismutase-1 (SOD1) and lipid membranes might be directly involved in the toxicity and intercellular propagation of aggregated SOD1 in amyotrophic lateral sclerosis (ALS), but the chemical details of lipid–SOD1 interactions and their effects on SOD1 aggregation remain unclear. This paper determined the rate and mechanism of nucleation of fibrillar apo-SOD1 catalyzed by liposomal surfaces with identical hydrophobic chains (RCH₂(O₂C₁₈H₃₃)₂), but headgroups of different net charge and hydrophobicity (i.e., R(CH₂)N⁺(CH₃)₃, RPO₄^–(CH₂)₂N⁺(CH₃)₃, and RPO₄^–). Under semiquiescent conditions (within a 96 well microplate, without a gyrating bead), the aggregation of apo-SOD1 into thioflavin-T-positive (ThT(+)) amyloid fibrils did not occur over 120 h in the absence of liposomal surfaces. Anionic liposomes triggered aggregation of apo-SOD1 into ThT(+) amyloid fibrils; cationic liposomes catalyzed fibrillization but at slower rates and across a narrower lipid concentration; zwitterionic liposomes produced nonfibrillar (amorphous) aggregates. The inability of zwitterionic liposomes to catalyze fibrillization and the dependence of fibrillization rate on anionic lipid concentration suggests that membranes catalyze SOD1 fibrillization by a primary nucleation mechanism. Membrane-catalyzed fibrillization was also examined for eight ALS variants of apo-SOD1, including G37R, G93R, D90A, and E100G apo-SOD1 that nucleate slower than or equal to WT SOD1 in lipid-free, nonquiescent amyloid assays. All ALS variants (with one exception) nucleated faster than WT SOD1 in the presence of anionic liposomes, wherein the greatest acceleratory effects were observed among variants with lower net negative surface charge (G37R, G93R, D90A, E100G). The exception was H46R apo-SOD1, which did not form ThT(+) species.

中文翻译：

---

甘油脂头基控制率和超氧化物歧化酶-1聚集和缓慢聚集的肌萎缩性肌萎缩侧索硬化突变体的加速原纤化的机制。

超氧化物歧化酶-1（SOD1）和脂质膜之间的相互作用可能直接参与了肌萎缩性侧索硬化症（ALS）中聚集的SOD1的毒性和细胞间传播，但脂质-SOD1相互作用的化学细节及其对SOD1聚集的影响尚不清楚。本文确定了具有相同疏水链（RCH ₂（O ₂ C ₁₈ H ₃₃）₂），但净电荷和疏水性不同的头基（R（CH）₂）N ⁺（CH ₃）₃，RPO ₄ ^–（CH₂）₂ N ⁺（CH ₃）₃和RPO ₄ ^–）。在半静态条件下（在96孔微孔板内，没有旋转珠），在没有脂质体表面的情况下，在120小时内apo-SOD1不会聚集到硫代黄素T阳性（ThT（+））淀粉样原纤维中。阴离子脂质体触发apo-SOD1聚集到ThT（+）淀粉样原纤维中；阳离子脂质体催化原纤维化，但速率较慢且脂质浓度较窄。两性离子脂质体产生非原纤维（无定形）聚集体。两性离子脂质体不能催化原纤维化以及原纤维化速率对阴离子脂质浓度的依赖性表明膜通过主要成核机制催化SOD1原纤维化。还检查了apo-SOD1的8种ALS变体的膜催化原纤维化，包括G37R，G93R，D90A，和E100G apo-SOD1在无脂质，非静态淀粉样蛋白分析中成核的速度慢于或等于WT SOD1。在存在阴离子脂质体的情况下，所有ALS变体（一个例外）的成核速度均比WT SOD1快，其中在具有较低净负表面电荷的变体（G37R，G93R，D90A，E100G）中观察到最大的促进作用。H46R apo-SOD1是例外，它没有形成ThT（+）物种。