BACKGROUND 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. RESULTS We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the (962)NGR-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. CONCLUSIONS 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.

中文翻译：

---

帕金森病-脑脊髓液中的铜蓝蛋白功能改变。

背景技术血浆铜蓝蛋白是脑脊液（CSF）中存在的一种亚铁氧化酶，在铁稳态中保护组织免受氧化损伤。在帕金森氏病（PD）中据报道其酶活性降低，这有助于病理性铁蓄积。我们以前表明，铜蓝蛋白在体内被氧化修饰，此外，体外还通过特定的NGR基序脱酰胺作用来促进整联蛋白结合功能的获得。在这里，我们调查了PD患者脑脊液中铜蓝蛋白亚铁氧化酶活性的丧失是否伴有NGR基序脱酰胺和功能获得。结果我们发现，PD患者脑脊液中的内源性铜蓝蛋白显示结构变化，通常隐藏在铜蓝蛋白结构中的（962）NGR基团脱酰胺，和整合素结合功能的获得。由于我们在PD患者的CSF中检测到异常水平的过氧化氢，因此出现了这些影响。有趣的是，PD患者的病理CSF环境在外源添加的铜蓝蛋白中促进了相同的修饰，进而导致亚铁氧化酶活性的丧失和整联蛋白结合特性的获得。结论我们表明，在PD-CSF的病理氧化环境中，除铁氧化酶功能丧失外，内源性铜蓝蛋白还被修饰以获得整联蛋白结合功能。这些发现，除了铜蓝蛋白在铁稳态中的已知作用外，由于潜在触发中枢神经系统细胞中整合素异常结合所介导的信号，可能具有重要的致病意义。