Laboratory of Neurodegenerative Diseases, Institut Francois Jacob (MIRCen), CNRS, CEA, University Paris-Saclay, Fontenay-Aux-Roses Cedex, France.
Laboratory of Neurodegenerative Diseases, Institut Francois Jacob (MIRCen), CNRS, CEA, University Paris-Saclay, Fontenay-Aux-Roses Cedex, France.
J Biol Chem. 2021 Jan-Jun;296:100737. doi: 10.1016/j.jbc.2021.100737. Epub 2021 Apr 30.
Synucleinopathies are neurodegenerative diseases characterized by the presence of intracellular deposits containing the protein alpha-synuclein (aSYN) within patients' brains. It has been shown that aSYN can form structurally distinct fibrillar assemblies, also termed polymorphs. We previously showed that distinct aSYN polymorphs assembled in vitro, named fibrils, ribbons, and fibrils 91, differentially bind to and seed the aggregation of endogenous aSYN in neuronal cells, which suggests that distinct synucleinopathies may arise from aSYN polymorphs. In order to better understand the differential interactions of aSYN polymorphs with their partner proteins, we mapped aSYN polymorphs surfaces. We used limited proteolysis, hydrogen-deuterium exchange, and differential antibody accessibility to identify amino acids on their surfaces. We showed that the aSYN C-terminal region spanning residues 94 to 140 exhibited similarly high solvent accessibility in these three polymorphs. However, the N-terminal amino acid residues 1 to 38 of fibrils were exposed to the solvent, while only residues 1 to 18 within fibrils 91 were exposed, and no N-terminal residues within ribbons were solvent-exposed. It is likely that these differences in surface accessibility contribute to the differential binding of distinct aSYN polymorphs to partner proteins. We thus posit that the polypeptides exposed on the surface of distinct aSYN fibrillar polymorphs are comparable to fingerprints. Our findings have diagnostic and therapeutic potential, particularly in the prion-like propagation of fibrillar aSYN, as they can facilitate the design of ligands that specifically bind and distinguish between fibrillar polymorphs.
突触核蛋白病是一种神经退行性疾病，其特征是患者大脑中存在含有蛋白α-突触核蛋白（aSYN）的细胞内沉积物。已经表明，aSYN 可以形成结构上不同的纤维状组装体，也称为多态性。我们之前表明，在体外组装的不同 aSYN 多态体，命名为纤维、带状物和纤维 91，以不同的方式结合并引发神经元细胞内内源性 aSYN 的聚集，这表明不同的突触核蛋白病可能是由 aSYN 多态体引起的。为了更好地理解 aSYN 多态体与它们的伴侣蛋白的差异相互作用，我们绘制了 aSYN 多态体的表面图。我们使用有限的蛋白水解、氢氘交换和差异抗体可及性来鉴定它们表面上的氨基酸。我们表明，跨越残基 94 到 140 的 aSYN C 末端区域在这三种多态体中表现出相似的高溶剂可及性。然而，纤维中的 aSYN N 端氨基酸残基 1 到 38 暴露于溶剂中，而纤维 91 中的仅残基 1 到 18 暴露于溶剂中，带状物中的无 N 端残基暴露于溶剂中。这些表面可及性的差异很可能导致不同的 aSYN 多态体与伴侣蛋白的差异结合。因此，我们假设，在不同的 aSYN 纤维状多态体表面暴露的多肽类似于指纹。我们的发现具有诊断和治疗潜力，特别是在纤维状 aSYN 的类朊病毒样传播中，因为它们可以促进设计专门结合和区分纤维状多态体的配体。
