Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India.
IITB-Monash Research Academy, IIT Bombay, Powai, Mumbai, 400076, India.
Angew Chem Int Ed Engl. 2018 May 4;57(19):5262-5266. doi: 10.1002/anie.201711854. Epub 2018 Apr 14.
α-Synuclein (α-Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomers versus fibrils in neuronal cell death is debatable, but recent studies suggest oligomers are a proximate neurotoxin. Herein, we show that soluble α-Syn monomers undergo a transformation from a solution to a gel state on incubation at high concentration. Detailed characterization of the gel showed the coexistence of monomers, oligomers, and short fibrils. In vitro, the gel was highly cytotoxic to human neuroblastoma cells. The individual constituents of the gel are short-lived species but toxic to the cells. They comprise a structurally heterogeneous population of α-helical and β-sheet-rich oligomers and short fibrils with the cross-β motif. Given the recent evidence of the gel-like state of the protein associated with neurodegenerative diseases, the gel state of α-Syn in this study represents a mechanistic and structural model for the in vivo toxicity of α-Syn in PD.
α-突触核蛋白（α-Syn）聚集与帕金森病（PD）的发病机制有关。在 PD 中，寡聚体与纤维在神经元细胞死亡中的作用存在争议，但最近的研究表明寡聚体是一种接近的神经毒素。在此，我们表明可溶性α-Syn 单体在高浓度孵育时会从溶液状态转变为凝胶状态。对凝胶的详细特征分析表明，单体、寡聚体和短纤维同时存在。在体外，凝胶对人神经母细胞瘤细胞具有高度细胞毒性。凝胶的各个成分都是寿命较短的物质，但对细胞有毒。它们包含具有交叉-β结构的结构异构的α-螺旋和β-折叠丰富的寡聚体和短纤维。鉴于最近与神经退行性疾病相关的蛋白凝胶状状态的证据，本研究中α-Syn 的凝胶状态代表了 PD 中α-Syn 体内毒性的一种机制和结构模型。
