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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尽管膜亲和力相似，但突触小泡模拟物对野生型和 A53T α-突触核蛋白变体的聚集的影响不同。


α-突触核蛋白错误折叠导致帕金森病中淀粉样原纤维的积累。错义蛋白突变（例如A53T）与早发性疾病有关。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发挥什么作用。在这里，我们比较了小单层囊泡（脂质成分与突触囊泡相似）对野生型 (WT) 和 A53T α-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与囊泡的结合亲和力相似，并且两者都与平行于膜表面的螺旋长轴相互作用。尽管如此，囊泡对变体聚集的影响不同：对于 WT 来说，对次级过程（例如断裂）的影响占主导地位，而对于 A53T 来说，原纤维伸长受到的影响最大。我们推测，除了单体结合之外，囊泡与聚集中间体的相互作用在 WT 和 A53T 之间也有所不同，从而导致淀粉样蛋白形成的不同后果。