α-Synuclein Oligomers Induced by Docosahexaenoic Acid Affect Membrane Integrity
α-Synuclein Oligomers Induced by Docosahexaenoic Acid Affect Membrane Integrity
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DOI：
10.1371/journal.pone.0082732
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发表时间：
2013-11-29
期刊：
影响因子：
3.7
通讯作者：
de Laureto, Patrizia Polverino
中科院分区：
文献类型：
--
作者：
Fecchio, Chiara;De Franceschi, Giorgia;de Laureto, Patrizia Polverino
帕金森病的一个关键特征是α-突触核蛋白的聚集及其以纤维形式的细胞内沉积。越来越多的证据表明，α-突触核蛋白的致病性与在其聚集过程的早期阶段形成的寡聚体的活性相关。低聚物的毒性似乎与它们结合脂膜和影响脂膜完整性的能力有关。先前，我们证明了α-突触核蛋白在二十二碳六烯酸存在下形成寡聚物种类，并且这些种类对细胞有毒。在这里，我们研究了这些低聚物与膜的相互作用如何导致细胞毒性，使用细胞膜模拟和细胞模型系统。我们发现，α-突触核蛋白寡聚体能够与大的和小的单层带负电荷的囊泡相互作用，获得增加量的α-螺旋结构，这诱导小分子释放。我们探讨了低聚物对膜的影响可能是由于孔的形成，洗涤剂样的效果或纤维生长的膜上的可能性。我们的生物物理和细胞的研究结果是一致的模型，其中α-突触核蛋白寡聚体嵌入到脂质双层引起膜通透性的瞬时改变。
A key feature of Parkinson disease is the aggregation of alpha-synuclein and its intracellular deposition in fibrillar form. Increasing evidence suggests that the pathogenicity of alpha-synuclein is correlated with the activity of oligomers formed in the early stages of its aggregation process. Oligomers toxicity seems to be associated with both their ability to bind and affect the integrity of lipid membranes. Previously, we demonstrated that alpha-synuclein forms oligomeric species in the presence of docosahexaenoic acid and that these species are toxic to cells. Here we studied how interaction of these oligomers with membranes results in cell toxicity, using cellular membrane-mimetic and cell model systems. We found that alpha-synuclein oligomers are able to interact with large and small unilamellar negatively charged vesicles acquiring an increased amount of alpha-helical structure, which induces small molecules release. We explored the possibility that oligomers effects on membranes could be due to pore formation, to a detergent-like effect or to fibril growth on the membrane. Our biophysical and cellular findings are consistent with a model where alpha-synuclein oligomers are embedded into the lipid bilayer causing transient alteration of membrane permeability.