Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Institut de Recerca en Ciències de la Salut (IdISBa), Departament de Química , Universitat de les Illes Balears , Ctra. Valldemossa km 7.5 , E-07122 Palma de Mallorca , Spain.
ACS Chem Neurosci. 2019 Jun 19;10(6):2919-2930. doi: 10.1021/acschemneuro.9b00142. Epub 2019 Apr 22.
Human α-synuclein is a small monomeric protein (140 residues) essential to maintain the function of the dopaminergic neurons and the neuronal redox balance. However, it holds a dark side since it is able to clump inside the neurons forming insoluble aggregates known as Lewy bodies, which are considered the hallmark of Parkinson's disease. Sporadic mutations and nonenzymatic post-translational modifications are well-known to stimulate the formation of Lewy bodies. Yet, the effect of nonenzymatic post-translational modifications on the function of α-synuclein has been studied less intense. Therefore, here we study how nitration and glycation mediated by methylglyoxal affect the redox features of α-synuclein. Both diminish the ability of α-synuclein to chelate Cu, except when N-(carboxyethyl)lysine or N-(carboxymethyl)lysine (two advanced glycation end products highly prevalent in vivo) are formed. This results in a lower capacity to prevent the Cu-catalyzed ascorbic acid degradation and to delay the formation of HO. However, only methylglyoxal was able to abolish the ability of α-synuclein to inhibit the free radical release. Both nitration and glycation enhanced the α-synuclein availability to be damaged by O, although glycation made α-synuclein less reactive toward HO. Our data represent the first report describing how nonenzymatic post-translational modifications might affect the redox function of α-synuclein, thus contributing to a better understanding of its pathological implications.
人源α-突触核蛋白是一种小的单体蛋白（140 个残基），对于维持多巴胺能神经元的功能和神经元的氧化还原平衡至关重要。然而，它也有黑暗的一面，因为它能够在神经元内聚集，形成不溶性聚集体，即路易体，被认为是帕金森病的标志。散发性突变和非酶翻译后修饰已知能刺激路易体的形成。然而，非酶翻译后修饰对α-突触核蛋白功能的影响研究得还不够深入。因此，在这里我们研究了由甲基乙二醛介导的硝化和糖化如何影响α-突触核蛋白的氧化还原特性。这两种修饰都降低了α-突触核蛋白螯合 Cu 的能力，除非形成 N-（羧乙基）赖氨酸或 N-（羧甲基）赖氨酸（两种在体内高度普遍存在的晚期糖基化终产物）。这导致其阻止 Cu 催化抗坏血酸降解和延迟 HO 形成的能力降低。然而，只有甲基乙二醛能够消除α-突触核蛋白抑制自由基释放的能力。硝化和糖化都增强了α-突触核蛋白被 O 损伤的可及性，尽管糖化使α-突触核蛋白对 HO 的反应性降低。我们的数据代表了首次描述非酶翻译后修饰如何影响α-突触核蛋白氧化还原功能的报告，从而有助于更好地理解其病理意义。
