Functional relevance of ceruloplasmin mutations in Parkinson's Disease
Functional relevance of ceruloplasmin mutations in Parkinson's Disease
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DOI：
10.1096/fj.04-3486fje
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发表时间：
2005-09-01
期刊：
影响因子：
4.8
通讯作者：
Berg, D
中科院分区：
文献类型：
--
作者：
Hochstrasser, H;Tomiuk, J;Berg, D
帕金森氏病(PD)患者黑质中铁水平的升高和铜蓝蛋白突变的发现表明，这种神经退行性疾病中的铁代谢受损。铜蓝蛋白具有铁氧合酶活性，可将铁(II)氧化为铁(III)。本研究分析了携带铜蓝蛋白突变I63T、D544E和R793H的帕金森病患者血清铜蓝蛋白、铁、铁蛋白和转铁蛋白的含量及铜蓝蛋白铁氧合酶活性。在细胞培养实验中研究了这些错义突变对全铜蓝蛋白生物合成的影响。铜蓝蛋白突变I63T和D544E存在功能相关性。在体内，I63T突变导致了正常铜蓝蛋白浓度的一半，并显著降低了异基因PD患者血清中铁氧合酶的活性。在细胞培养中，I63T糖基磷脂酰肌醇(GPI)连接的铜蓝蛋白亚型保留在人胚胎肾细胞的内质网中。此外，D544E基因多态导致异位基因携带者血清铜蓝蛋白水平和铁氧合酶活性显著降低，细胞培养中主要表达载铜蛋白。我们的研究表明，铜蓝蛋白活性的改变可能是铁诱导帕金森病氧化应激的一个易损性因素。
Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.