Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, London, W12 0BZ, UK.
Nat Commun. 2021 Feb 10;12(1):927. doi: 10.1038/s41467-021-21027-4.
α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson's disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.
α-突触核蛋白（αS）是一种突触前的无序蛋白，其异常聚集与帕金森病有关。尽管 αS 已被涉及通过与突触小泡（SVs）的相互作用来调节神经递质释放，但它的功能作用仍存在争议。我们使用小单层囊泡，在此报道了与突触前质膜（PM）的内、外叶结合的 αS 的构象特性的详细特征。我们的结果表明，αS 优先结合内 PM 叶。基于这些研究，我们在体外研究了一种机制，即 αS 通过在两个膜之间建立动态连接，以浓度依赖的方式稳定 SV 停靠在 PM 上，从而稳定 SV 停靠在 PM 上。然后，该研究提供了证据表明 PM 的脂质组成发生变化，通常与神经退行性疾病有关，改变了 αS 的结合模式，特别是在与非淀粉样成分区域重叠的序列片段中。总之，这些结果揭示了脂质组成如何调节 αS 与 PM 的相互作用，并阐明了其在体外的功能和病理行为。
