PDF(Pubmed)
Abstract：
Parkinson\'s disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.
摘要：
帕金森病（PD）是一种日益普遍且目前无法治愈的神经退行性疾病，与神经系统中α-突触核蛋白（αS）蛋白聚集体的积累有关。虽然αS在其单体状态下与膜结合与其生理作用相关，αS寡聚化和随后与脂质双层的异常相互作用已成为PD相关神经毒性的关键步骤。然而,控制寡聚αS（OαS）与脂质膜相互作用的机制以及调节这种相互作用的因素知之甚少。这在很大程度上是由于OαS-膜相互作用的动态和瞬时性质的基础研究的实验挑战。这里,我们通过使用一套基于微流体的测定法来解决这一挑战,这些测定法能够在溶液中定量OαS-膜相互作用.我们发现OαS与高度弯曲的结合更强，而不是平坦的，脂质膜。通过比较OαS和单体αS（MαS）的膜结合特性，我们进一步证明OαS与膜结合的亲和力比它们的单体对应物高150倍。此外，OαS与膜表面竞争并从膜表面置换结合的MαS，表明破坏MαS与膜的功能结合可能在PD中提供额外的毒性机制。这些发现提出了低聚物与模型膜的结合机制，这可能是潜在的目标，以抑制PD的进展。
