Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, United States of America; Bruker Nano Surfaces Division, 112 Robin Hill Road, Goleta, Santa Barbara, CA 93117, United States of America.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, United States of America.
Biochim Biophys Acta Proteins Proteom. 2019 Sep;1867(9):802-812. doi: 10.1016/j.bbapap.2019.06.006. Epub 2019 Jun 19.
The spontaneous self-assembly of α-synuclein (α-syn) into aggregates of different morphologies is associated with the development of Parkinson's disease. However, the mechanism behind the spontaneous assembly remains elusive. The current study shows a novel effect of phospholipid bilayers on the assembly of the α-syn aggregates. Using time-lapse atomic force microscopy, it was discovered that α-syn assembles into aggregates on bilayer surfaces, even at the nanomolar concentration range. The efficiency of the aggregation process depends on the membrane composition, with the greatest efficiency observed for of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS). Importantly, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation is a mechanism by which pathological aggregates may be produced. Computational modeling revealed that dimers of α-syn assembled rapidly, through the membrane-bound monomer on POPS bilayer, due to an aggregation-prone orientation of α-syn. Interaction of α-syn with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) leads to a binding mode that does not induce a fast assembly of the dimer. Based on these findings, we propose a model in which the interaction of α-syn with membranes plays a critical role initiating the formation of α-syn aggregates and the overall aggregation process.
α- 突触核蛋白（α-syn）自发自组装成不同形态的聚集体与帕金森病的发展有关。然而，自发组装的机制仍不清楚。本研究显示了磷脂双层对 α-syn 聚集体组装的一种新影响。通过实时原子力显微镜发现，α-syn 即使在纳摩尔浓度范围内也会在双层表面上组装成聚集体。聚合过程的效率取决于膜的组成，其中 1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸-l-丝氨酸（POPS）的效率最高。重要的是，组装的聚集体可以从表面上解离，这表明表面上的聚集是病理性聚集体可能产生的一种机制。计算模型表明，由于 α-syn 的聚集倾向取向，α-syn 通过膜结合单体在 POPS 双层上快速组装成二聚体。α-syn 与 1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱（POPC）的相互作用导致不诱导二聚体快速组装的结合模式。基于这些发现，我们提出了一个模型，其中 α-syn 与膜的相互作用在启动 α-syn 聚集体形成和整体聚合过程中起着关键作用。
