Lipid bilayer disruption by oligomeric alpha-synuclein depends on bilayer charge and accessibility of the hydrophobic core.
Lipid bilayer disruption by oligomeric alpha-synuclein depends on bilayer charge and accessibility of the hydrophobic core.
复制标题
DOI：
10.1016/j.bbamem.2009.03.010
复制
发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
B. V. van Rooijen;M. Claessens;V. Subramaniam
中科院分区：
文献类型：
--
作者：
B. V. van Rooijen;M. Claessens;V. Subramaniam
α-突触核蛋白的可溶性寡聚聚集体在帕金森病的发病机制中发挥着核心作用。 α-突触核蛋白寡聚体对脂质双层的破坏和透化被认为是一种毒性机制，但控制寡聚体-膜相互作用的分子细节仍然未知。在这里，我们表明膜破坏很大程度上取决于疏水膜核心的可及性，并且电荷相互作用起着重要但复杂的作用。我们使用染料释放测定系统地研究了物理膜特性和溶液条件对低聚物破坏脂质双层的影响。改变脂质头基组成表明，膜破裂仅发生在带负电的双层上。此外，带负电的 α-突触核蛋白和双层的负表面电荷之间的静电排斥会在低离子强度下抑制囊泡破裂。带负电的囊泡的破坏进一步取决于脂质堆积参数。双层组成的变化导致脂质头基间距增加，使囊泡更容易破裂，这表明双层烃核心的可及性调节寡聚物-膜相互作用。这些数据为控制备受争议的低聚物-膜相互作用过程的驱动力提供了重要的新见解。
Soluble oligomeric aggregates of α-synuclein have been implicated to play a central role in the pathogenesis of Parkinson's disease. Disruption and permeabilization of lipid bilayers by α-synuclein oligomers is postulated as a toxic mechanism, but the molecular details controlling the oligomer–membrane interaction are still unknown. Here we show that membrane disruption strongly depends on the accessibility of the hydrophobic membrane core and that charge interactions play an important but complex role. We systematically studied the influence of the physical membrane properties and solution conditions on lipid bilayer disruption by oligomers using a dye release assay. Varying the lipid headgroup composition revealed that membrane disruption only occurs for negatively charged bilayers. Furthermore, the electrostatic repulsion between the negatively charged α-synuclein and the negative surface charge of the bilayer inhibits vesicle disruption at low ionic strength. The disruption of negatively charged vesicles further depends on lipid packing parameters. Bilayer composition changes that result in an increased lipid headgroup spacing make vesicles more prone to disruption, suggesting that the accessibility of the bilayer hydrocarbon core modulates oligomer–membrane interaction. These data shed important new insights into the driving forces governing the highly debated process of oligomer–membrane interactions.