Formation of dopamine-mediated α-synuclein-soluble oligomers requires methionine oxidation
Formation of dopamine-mediated α-synuclein-soluble oligomers requires methionine oxidation
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DOI：
10.1016/j.freeradbiomed.2009.02.009
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发表时间：
2009-05-15
影响因子：
7.4
通讯作者：
Cappai, Roberto
中科院分区：
文献类型：
--
作者：
Leong, Su Ling;Pham, Chi L. L.;Cappai, Roberto
α-突触核蛋白是帕金森病(PD)神经元细胞内路易体包涵体的主要成分。帕金森病包括黑质多巴胺能神经元的丢失和纹状体多巴胺的耗竭。DA在体外可抑制α-突触核蛋白的纤化，促进α-突触核蛋白聚集成可溶性低聚物。我们研究了DA介导α-突触核蛋白聚集成可溶性低聚物的机制。α-突触核蛋白与DA的反应增加了α-突触核蛋白的质量，达。核磁共振结果表明，四个蛋氨酸残基均被DA氧化，这与大的加入一致。将所有四种蛋氨酸替换为丙氨酸，可显著减少DA介导的可溶性低聚物的形成。α-突触核蛋白的(YEMPS129)-Y-125基序可以调节DA对α-突触核蛋白纤化的抑制作用。然而，在(YEMPS129)-Y-125基序(残基1-124)之前结束的α-突触核蛋白仍然可以形成可溶性低聚物。外源合成的YEMPS多肽的加入抑制了可溶性低聚体的形成，导致YEMPS多肽被氧化。因此，(YEMPS129)-Y-125作为一种抗氧化剂父亲而不是直接与DA相互作用。我们的研究将蛋氨酸氧化定义为DA产生可溶性α-突触核蛋白寡聚体的主要机制，并强调了氧化应激在调节α-突触核蛋白聚集中的潜在作用。(C)2009 Elsevier Inc.保留所有权利。
alpha-Synuclein is the major component of the intracellular Lewy body inclusions present in Parkinson disease (PD) neurons. PD involves the loss of dopaminergic neurons in the substantia nigra and the subsequent depletion of dopamine (DA) in the striatum. DA can inhibit alpha-synuclein fibrillization in vitro and promote alpha-synuclein aggregation into Soluble oligomers. We have studied the mechanism by which DA mediates alpha-synuclein aggregation into soluble oligomers. Reacting alpha-synuclein with DA increased the mass of alpha-synuclein by 64 Da. NMR showed that all four methionine residues were oxidized by DA, consistent with the addition of 64 Da. Substituting all four methionines to alanine significantly reduced the formation of DA-mediated soluble oligomers. The (YEMPS129)-Y-125 motif in alpha-synuclein can modulate DA inhibition of alpha-synuclein fibrillization. However, alpha-synuclein ending before the (YEMPS129)-Y-125 motif (residues 1-124) could still form soluble oligomers. The addition of exogenous synthetic YEMPS peptide inhibited the formation of soluble oligomers and resulted in the YEMPS peptide being oxidized. Therefore, the (YEMPS129)-Y-125 acts as an antioxidant Father than interacting directly with DA. Our study defines methionine oxidation as the dominant mechanism by which DA generates soluble alpha-synuclein oligomers and highlights the potential role for oxidative stress in modulating alpha-synuclein aggregation. (C) 2009 Elsevier Inc. All rights reserved.