The intracellular α-synuclein (α-syn) protein, whose conformational change and aggregation have been closely linked to the pathology of Parkingson's disease (PD), is highly populated at the presynaptic termini and remains there in the α-helical conformation. In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol (TFE). Electrochemical and UV-visible spectroscopic experiments reveal that both Cu (I) and Cu (II) are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn (Binolfi et al., J. Am. Chem. Soc. 133 (2011) 194-196), α-helical α-syn stabilizes Cu (I) by more than three orders of magnitude. Through the measurements of H(2)O(2) and hydroxyl radicals (OH) in solutions containing different forms of Cu (II) (free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu (I) binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured α-syn to its α-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.

译文

细胞内 α-突触核蛋白 (α-syn) 蛋白的构象变化和聚集与Parkingson病 (PD) 的病理密切相关,在突触前末端高度聚集,并保留在 α-螺旋构象中。在这项研究中,圆二色性证实,加入三氟乙醇 (TFE) 后,水溶液中的原生非结构化 α-syn转化为其 α-螺旋构象。电化学和紫外可见光谱实验表明,Cu (I) 和Cu (II) 都是稳定的,前者稳定了大约两个数量级。与非结构化 α-syn (Binolfi等人,J. Am. Chem. Soc. 133 (2011) 194-196) 相比,α-螺旋 α-syn使Cu (I) 稳定超过三个数量级。通过测量含有不同形式的Cu (II) (游离并通过非结构化或 α-螺旋 α-syn络合) 的溶液中的H(2)O(2) 和羟基自由基 (OH),我们证明了显着增强的Cu (I) 结合亲和力有助于抑制高毒性活性氧的产生,尤其是羟基自由基。我们的研究提供了有力的证据,表明作为防止神经元细胞损伤的一种可能手段,在体内将非结构化的 α-syn转化为其 α-螺旋构象可以显着减弱铜调节的ROS的产生。

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