Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy.
Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy.
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DOI：
10.3390/life11050431
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发表时间：
2021-05-11
期刊：
影响因子：
--
通讯作者：
Cecchi C
中科院分区：
文献类型：
--
作者：
Bigi A;Ermini E;Chen SW;Cascella R;Cecchi C
α-突触核蛋白（α-Synuclein，αS）是一种高度动态的蛋白质，参与突触前末梢多巴胺的释放。αS作为成熟原纤维异常聚集成神经元内包涵体与帕金森病直接相关。越来越多的实验证据表明，在聚集过程早期形成的可溶性低聚物是αS最具细胞毒性的形式。本研究利用一系列构象敏感性抗体和超分辨率受激发射耗尽（STED）显微镜研究了神经细胞对病理相关αS寡聚体和原纤维的摄取。我们发现，prefibrillar寡聚体迅速穿透神经元膜，从而导致细胞功能障碍。相比之下，原纤维对接到磷脂双分子层伴随着αS构象变化，伴随着A11反应性寡聚体的逐步释放，其可以进入神经元并触发细胞损伤。我们的数据为αS纤维作为有害低聚物来源的作用提供了重要证据，这些低聚物类似于聚集过程中从头形成的中间构象体，这是导致α-突触核蛋白病的蛋白质聚集体的动态和可逆性质的基础。
α-Synuclein (αS) is an intrinsically disordered and highly dynamic protein involved in dopamine release at presynaptic terminals. The abnormal aggregation of αS as mature fibrils into intraneuronal inclusion bodies is directly linked to Parkinson’s disease. Increasing experimental evidence suggests that soluble oligomers formed early during the aggregation process are the most cytotoxic forms of αS. This study investigated the uptake by neuronal cells of pathologically relevant αS oligomers and fibrils exploiting a range of conformation-sensitive antibodies, and the super-resolution stimulated emission depletion (STED) microscopy. We found that prefibrillar oligomers promptly penetrate neuronal membranes, thus resulting in cell dysfunction. By contrast, fibril docking to the phospholipid bilayer is accompanied by αS conformational changes with a progressive release of A11-reactive oligomers, which can enter into the neurons and trigger cell impairment. Our data provide important evidence on the role of αS fibrils as a source of harmful oligomers, which resemble the intermediate conformers formed de novo during aggregation, underling the dynamic and reversible nature of protein aggregates responsible for α-synucleinopathies.
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影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
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：
16.6
作者：
Cascella R;Chen SW;Bigi A;Camino JD;Xu CK;Dobson CM;Chiti F;Cremades N;Cecchi C
通讯作者：
Cecchi C
影响因子：
8.8
作者：
Brehme M;Voisine C;Rolland T;Wachi S;Soper JH;Zhu Y;Orton K;Villella A;Garza D;Vidal M;Ge H;Morimoto RI
通讯作者：
Morimoto RI
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