The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells.
The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells.
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DOI：
10.1038/s41467-021-21937-3
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发表时间：
2021-03-22
影响因子：
16.6
通讯作者：
Cecchi C
中科院分区：
文献类型：
--
作者：
Cascella R;Chen SW;Bigi A;Camino JD;Xu CK;Dobson CM;Chiti F;Cremades N;Cecchi C
α-突触核蛋白(αS)自组装成神经元内包涵体是帕金森病的一个关键特征。为了确定导致神经元损伤的物种的性质，我们调查了主要的αS种群的作用机制，这些种群被观察到在纤维生长过程中逐渐形成。αS纤维释放出具有交叉β结构和暴露在溶剂中的疏水团簇的可溶性前纤维低聚物物种。αS前纤维低聚物能有效地穿透神经细胞膜，造成细胞损伤。短纤维比长纤维具有更强的神经毒性，因为纤维末端的比例较高，导致寡聚体迅速释放。αS低聚物的释放动力学与细胞系统中观察到的毒性动力学相吻合。除了先前的证据表明αS纤维可以扩散到不同的大脑区域外，我们的体外结果还表明，αS纤维还可以释放导致这些物种附近神经元立即功能障碍的寡聚体物种。α-突触核蛋白(αS)的自组装是帕金森病的病理特征。负责神经元损伤的αS种的特征还不是很好。在这里，作者证明了αS纤维在体外释放了与神经毒性有关的可溶性前纤维低聚物。
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. The self-assembly of α-synuclein (αS) is a pathological feature of Parkinson’s disease. The αS species responsible for neuronal damage are not well characterized. Here, the authors show that αS fibrils release soluble prefibrillar oligomeric species responsible for neurotoxicity in vitro.
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影响因子：
4
作者：
Angelova PR;Ludtmann MH;Horrocks MH;Negoda A;Cremades N;Klenerman D;Dobson CM;Wood NW;Pavlov EV;Gandhi S;Abramov AY
通讯作者：
Abramov AY
影响因子：
4.6
作者：
Fusco G;De Simone A;Arosio P;Vendruscolo M;Veglia G;Dobson CM
通讯作者：
Dobson CM
DOI：
10.1073/pnas.1421204112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Chen, Serene W.;Drakulic, Srdja;Cremades, Nunilo
通讯作者：
Cremades, Nunilo
影响因子：
4.8
作者：
Froula, Jessica M.;Castellana-Cruz, Marta;Volpicelli-Daley, Laura A.
通讯作者：
Volpicelli-Daley, Laura A.
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A