DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease
DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease
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DOI：
10.1093/brain/awq008
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发表时间：
2010-03-01
期刊：
影响因子：
14.5
通讯作者：
Zhang, Jing
中科院分区：
文献类型：
--
作者：
Hong, Zhen;Shi, Min;Zhang, Jing
帕金森病的诊断和疾病进展的监测迫切需要生物标志物。DJ-1和α-突触核蛋白，两种与帕金森病发病机制密切相关的蛋白质，已在最近的几项研究中作为疾病生物标志物进行了测试，结果不一致。这在很大程度上是由于不同抗体检测到的蛋白质种类的变化，一些研究中患者数量有限，或对几个重要变量的控制不足。在这项研究中，DJ-1和α-突触核蛋白在人类脑脊液的性质进行了研究，结合蛋白质印迹，凝胶过滤和质谱。建立了检测人脑脊液中大多数（如果不是全部）DJ-1和α-突触核蛋白的灵敏定量Luminex测定法。使用新开发的高灵敏度Luminex技术分析了117名帕金森病患者、132名健康个体和50名阿尔茨海默病患者的DJ-1和α-突触核蛋白的脑脊液浓度，同时控制了几个主要混杂因素。共分析了299个个体和389个样本。结果表明，脑脊液DJ-1和α-突触核蛋白水平依赖于年龄，并受到脑脊液中血液污染程度的影响。与对照组或阿尔茨海默病患者相比，当血液污染得到控制时，帕金森病患者的DJ-1和α-突触核蛋白水平均降低。在年龄≥ 65岁的人群中，当DJ-1和α-突触核蛋白分别选择40和0.5 ng/ml的截止值时，帕金森病患者与对照组相比，DJ-1的灵敏度和特异性分别为90和70%，α-突触核蛋白为92和58%。两种标记物的组合并没有提高测试性能。DJ-1或α-突触核蛋白与帕金森病的严重程度之间没有关联。总之，这代表了迄今为止对人类脑脊液中DJ-1或α-突触核蛋白的最大规模研究，同时使用新建立的灵敏Luminex测定法，并控制多个变量。我们已经证明，如果考虑到血液污染和年龄等变量，人类脑脊液中的总DJ-1和α-突触核蛋白是帕金森病的有用诊断标志物。
Biomarkers are urgently needed for the diagnosis and monitoring of disease progression in Parkinson's disease. Both DJ-1 and alpha-synuclein, two proteins critically involved in Parkinson's disease pathogenesis, have been tested as disease biomarkers in several recent studies with inconsistent results. These have been largely due to variation in the protein species detected by different antibodies, limited numbers of patients in some studies, or inadequate control of several important variables. In this study, the nature of DJ-1 and alpha-synuclein in human cerebrospinal fluid was studied by a combination of western blotting, gel filtration and mass spectrometry. Sensitive and quantitative Luminex assays detecting most, if not all, species of DJ-1 and alpha-synuclein in human cerebrospinal fluid were established. Cerebrospinal fluid concentrations of DJ-1 and alpha-synuclein from 117 patients with Parkinson's disease, 132 healthy individuals and 50 patients with Alzheimer's disease were analysed using newly developed, highly sensitive Luminex technology while controlling for several major confounders. A total of 299 individuals and 389 samples were analysed. The results showed that cerebrospinal fluid DJ-1 and alpha-synuclein levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid. Both DJ-1 and alpha-synuclein levels were decreased in Parkinson's patients versus controls or Alzheimer's patients when blood contamination was controlled for. In the population aged >= 65 years, when cut-off values of 40 and 0.5 ng/ml were chosen for DJ-1 and alpha-synuclein, respectively, the sensitivity and specificity for patients with Parkinson's disease versus controls were 90 and 70% for DJ-1, and 92 and 58% for alpha-synuclein. A combination of the two markers did not enhance the test performance. There was no association between DJ-1 or alpha-synuclein and the severity of Parkinson's disease. Taken together, this represents the largest scale study for DJ-1 or alpha-synuclein in human cerebrospinal fluid so far, while using newly established sensitive Luminex assays, with controls for multiple variables. We have demonstrated that total DJ-1 and alpha-synuclein in human cerebrospinal fluid are helpful diagnostic markers for Parkinson's disease, if variables such as blood contamination and age are taken into consideration.