CRIBI, Biotechnology Centre, Department of Pharmaceutical Sciences, University of Padova, Padova, Italy.
PLoS One. 2013 Nov 29;8(11):e82732. doi: 10.1371/journal.pone.0082732. eCollection 2013.
A key feature of Parkinson disease is the aggregation of α-synuclein and its intracellular deposition in fibrillar form. Increasing evidence suggests that the pathogenicity of α-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 α-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 α-synuclein oligomers are able to interact with large and small unilamellar negatively charged vesicles acquiring an increased amount of α-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 α-synuclein oligomers are embedded into the lipid bilayer causing transient alteration of membrane permeability.
帕金森病的一个主要特征是α-突触核蛋白的聚集及其在纤维形式中的细胞内沉积。越来越多的证据表明，α-突触核蛋白的致病性与其在聚集过程早期形成的寡聚物的活性有关。寡聚物的毒性似乎与其结合和影响脂质膜完整性的能力有关。此前，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，并且这些寡聚物对细胞有毒性。在这里，我们使用细胞膜类似物和细胞模型系统研究了这些寡聚物与膜的相互作用如何导致细胞毒性。我们发现α-突触核蛋白寡聚物能够与大的和小的带负电荷的单层囊泡相互作用，获得更多的α-螺旋结构，从而诱导小分子释放。我们探讨了寡聚物对膜的影响是否可能是由于孔形成、类似去污剂的作用或纤维在膜上的生长所致。我们的生物物理和细胞发现与这样一种模型一致，即α-突触核蛋白寡聚物嵌入脂质双层中，导致膜通透性的瞬时改变。
