Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.
Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.
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帕金森病脑脊液液中的Ceruloplasmin功能变化。
DOI：
10.1186/s13024-015-0055-2
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发表时间：
2015-11-04
影响因子：
15.1
通讯作者：
Alessio M
中科院分区：
文献类型：
--
作者：
Barbariga M;Curnis F;Andolfo A;Zanardi A;Lazzaro M;Conti A;Magnani G;Volontè MA;Ferrari L;Comi G;Corti A;Alessio M
血浆铜蓝蛋白是一种存在于脑脊液（CSF）中的铁氧化酶，在铁稳态中发挥作用，保护组织免受氧化损伤。据报道，其酶活性降低在帕金森病（PD）中有助于病理性铁积累。我们以前表明，铜蓝蛋白是通过在体内氧化修饰，此外，在体外通过脱酰胺的特定NGR-基序，促进整合素结合功能的增益。在这里，我们调查了是否在PD患者的CSF中的铜蓝蛋白铁氧化酶活性的损失是伴随着NGR基序脱酰胺和功能的增益。我们发现PD患者CSF中的内源性铜蓝蛋白表现出结构变化，通常隐藏在铜蓝蛋白结构内的962 NGR-基序的脱酰胺化，以及整合素结合功能的获得。这些影响的发生是由于我们在PD患者的CSF中检测到的过氧化氢水平异常。有趣的是，PD患者的病理性CSF环境促进了外源性添加的血浆铜蓝蛋白的相同修饰，这反过来又导致铁氧化酶活性的丧失和整合素结合特性的获得。我们发现，在病理氧化环境中的PD-CSF的内源性铜蓝蛋白，除了损失的铁氧化酶功能，被修改，以获得整合素结合功能。这些发现，除了已知的铜蓝蛋白在铁稳态的作用，可能有重要的致病性的影响，由于潜在的触发信号介导的不寻常的整合素结合在中枢神经系统的细胞。此外，存在药理学意义，因为基于在鼠模型中获得的数据，铜蓝蛋白给药已被提议作为PD的潜在治疗性治疗，然而，观察到的CSF的促氧化特性提高了在人体中基于铜蓝蛋白的治疗方法可能无效的可能性。本文的在线版本（doi：10.1186/s13024-015-0055-2）包含补充材料，可供授权用户使用。
Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson’s disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function. We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the 962NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties. We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious. The online version of this article (doi:10.1186/s13024-015-0055-2) contains supplementary material, which is available to authorized users.