Abstract：
Protein liquid-liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process of amyloid fibril formation, serving as an intermediate step between the native protein transition into their aggregated state. The formation of fibrils via LLPS has been demonstrated for a number of proteins related to neurodegenerative disorders, as well as other amyloidoses. Despite the surge in amyloid-related LLPS studies, the influence of protein condensate formation on the end-point fibril characteristics is still far from fully understood. In this work, we compare alpha-synuclein aggregation under different conditions, which promote or negate its LLPS and examine the differences between the formed aggregates. We show that alpha-synuclein phase separation generates a wide variety of assemblies with distinct secondary structures and morphologies. The LLPS-induced structures also possess higher levels of toxicity to cells, indicating that biomolecular condensate formation may be a critical step in the appearance of disease-related fibril variants.
摘要：
蛋白质液-液相分离（LLPS）是生物分子缩合物形成研究的一个新兴领域。近年来,这种现象与淀粉样蛋白原纤维形成过程有关，充当天然蛋白质转变为其聚集状态之间的中间步骤。通过LLPS形成的原纤维已被证明与神经退行性疾病有关的许多蛋白质，以及其他淀粉样蛋白。尽管淀粉样蛋白相关的LLPS研究激增，蛋白质缩合物形成对终点原纤维特性的影响还远未完全了解。在这项工作中,我们比较了不同条件下的α-突触核蛋白聚集，促进或否定其LLPS，并检查形成的骨料之间的差异。我们表明α-突触核蛋白相分离产生了具有不同二级结构和形态的多种组装体。LLPS诱导的结构对细胞也具有更高水平的毒性，这表明生物分子缩合物的形成可能是疾病相关原纤维变体出现的关键步骤。
