Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy.
Department of Life Science, Imperial College London, London, UK.
Nat Commun. 2021 Mar 22;12(1):1814. doi: 10.1038/s41467-021-21937-3.
The self-assembly of α-synuclein (αS) into intraneuronal inclusion bodies is a key characteristic of Parkinson's disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main αS populations that have been observed to form progressively during fibril growth. The αS fibrils release soluble prefibrillar oligomeric species with cross-β structure and solvent-exposed hydrophobic clusters. αS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released αS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that αS fibrils can spread in different brain areas, our in vitro results reveal that αS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species.
α-突触核蛋白（αS）自发聚集形成细胞内包涵体是帕金森病的一个关键特征。为了明确导致神经元损伤的物质种类，我们研究了在纤维生长过程中逐渐形成的主要 αS 聚集体的作用机制。αS 纤维释放具有交叉-β结构和暴露疏水性簇的可溶性原纤维寡聚物。αS 原纤维寡聚物能够有效地穿过并渗透神经元膜，导致细胞损伤。由于短纤维中纤维末端的比例更高，因此比长纤维具有更高的神经毒性，从而导致寡聚物的快速释放。释放的αS 寡聚物的动力学与细胞系统中观察到的毒性动力学相匹配。除了先前有证据表明 αS 纤维可以在不同的脑区扩散外，我们的体外结果还表明，αS 纤维也可以释放寡聚物，这些寡聚物会导致附近神经元的即刻功能障碍。
