α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson's disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

中文翻译：

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突触小泡模拟物虽然相似的膜亲和力，但对野生型和A53Tα-突触核蛋白变体的聚集产生不同的影响。

α-突触核蛋白的错误折叠导致帕金森氏病中淀粉样蛋白原纤维的积累。错义蛋白突变（例如A53T）与早期发病有关。尽管α-突触核蛋白与大脑中的突触小泡相互作用，但尚不清楚它们在蛋白质聚集过程中起什么作用。在这里，我们比较了小单层囊泡（脂质成分类似于突触囊泡）对野生型（WT）和A53Tα-突触核蛋白聚集的影响。使用生物物理技术，我们揭示了两种蛋白质对囊泡的结合亲和力相似，并且都与平行于膜表面的螺旋长轴相互作用。尽管如此，囊泡对变体的聚集产生不同的影响：对次要过程（例如片段化）的影响在WT中占主导地位，而对于A53T，原纤维的伸长率主要受到影响。我们推测，除了单体结合外，囊泡与聚集中间物种的相互作用除了在WT和A53T之间变化外，还导致淀粉样蛋白形成的不同结果。