The Reaction of α-Synuclein with Tyrosinase
The Reaction of α-Synuclein with Tyrosinase
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DOI：
10.1074/jbc.m709014200
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发表时间：
2008-06
影响因子：
4.8
通讯作者：
Isabella Tessari;M. Bisaglia;F. Valle;B. Samorì;E. Bergantino;S. Mammi;L. Bubacco
中科院分区：
文献类型：
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作者：
Isabella Tessari;M. Bisaglia;F. Valle;B. Samorì;E. Bergantino;S. Mammi;L. Bubacco
氧化应激似乎直接参与帕金森病的发病机制。已经确定了黑质多巴胺能神经元中产生氧化应激条件的几种不同途径，包括胞质多巴胺的病理性积累，随后产生毒性活性氧或形成高活性醌类。在这些前提下，酪氨酸酶，一种关键的铜酶，已知其在皮肤和头发中的黑色素合成中的作用，已被提出参与与帕金森病相关的氧化化学。本文研究了酪氨酸酶与α-突触核蛋白的体外反应性，旨在确定它们协同毒性作用的分子基础。结果表明，与酪氨酸酶的严格特异性一致，暴露的酪氨酸侧链是α-突触核蛋白的反应中心。α-突触核蛋白的反应性取决于它是游离的还是膜结合的，并且对酪氨酸酶处理的α-突触核蛋白的化学修饰强烈影响其聚集性质。在我们的研究结果的基础上，我们提出了一个细胞毒性模型，其中包括一个可能的新的毒性作用的α-突触核蛋白加剧其直接化学修饰的酪氨酸酶。
Oxidative stress appears to be directly involved in the pathogenesis of Parkinson disease. Several different pathways have been identified for the production of oxidative stress conditions in nigral dopaminergic neurons, including a pathological accumulation of cytosolic dopamine with the subsequent production of toxic reactive oxygen species or the formation of highly reactive quinone species. On these premises, tyrosinase, a key copper enzyme known for its role in the synthesis of melanin in skin and hair, has been proposed to take part in the oxidative chemistry related to Parkinson disease. A study is herein presented of the in vitro reactivity of tyrosinase with α-synuclein, aimed at defining the molecular basis of their synergistic toxic effect. The results presented here indicate that, in conformity with the stringent specificity of tyrosinase, the exposed tyrosine side-chains are the reactive centers of α-synuclein. The reactivity of α-synuclein depends on whether it is free or membrane bound, and the chemical modifications on the tyrosinase-treated α-synuclein strongly influence its aggregation properties. On the basis of our results, we propose a cytotoxic model which includes a possible new toxic role for α-synuclein exacerbated by its direct chemical modification by tyrosinase.