REDOX METAL IONS AND NEURONAL PROTEIN DEPOSITION

许多神经退行性疾病（包括阿尔茨海默病、帕金森病、亨廷顿病、朊病毒病和肌萎缩侧索硬化症）的共同神经病理特征是与脑内蛋白质沉积相关的氧化应激灶标记物的存在。与这些疾病共同的是许多铜蛋白，如淀粉样蛋白前体（APP）、朊蛋白、亨廷顿蛋白、单胺氧化酶和超氧化物歧化酶，它们与这些疾病的发病机制有关。最近，我们报道淀粉样蛋白的主要成分APP和Abeta以高亲和力结合氧化还原金属离子铜，并且这些蛋白能够还原Cu(II)，随后产生活性氧。因此，Abeta结合和还原Cu(II)（和Fe(III)）的能力产生了一种情况，即Abeta可能被化学修饰，并且可以解释在淀粉样斑块内和周围观察到的许多其他氧化修饰。事实上，我们已经证明，在氧化还原活性金属的存在下，β形成抗十二烷基硫酸钠的聚合物，就像从AD大脑中提取的聚合物一样。因此，最近报道的Abeta沉积物对金属离子的摄取可能导致氧化修饰，从而导致Abeta聚合物的形成和Abeta逐渐沉积到硬核淀粉样斑块中。可能类似的反应也会导致其他铜蛋白的沉积，这些铜蛋白沉积在神经退行性疾病中。这项研究旨在进一步表征金属离子与已知沉积在大脑中的蛋白质的结合，例如帕金森病的α -突触核蛋白，朊蛋白疾病的朊蛋白和阿尔茨海默病的Abeta。此外，使用标准的分析方法，我们将测试金属离子是否诱导α -突触核蛋白和PrP的聚集和/或聚合。最后，我们将尝试在这些蛋白质中定位可能解释聚合机制的化学修饰。这些数据对于确定神经元蛋白沉淀背后的机制将是重要的，并可能对如何防止它们在体内沉积产生见解。

A common neuropathological feature of many neurodegenerative diseases, including Alzheimer s disease, Parkinson s disease, Huntington s disease, prion diseases and amyotrophic lateral sclerosis is the presence of focal markers of oxidative stress associated with proteinaceous deposits within the brain. In common with these diseases are a number of cuproproteins such as amyloid protein precursor (APP), prion protein, Huntingtin protein, monoamine oxidase and superoxide dismutase, which are implicated in the pathogenesis of these diseases. Recently, we have reported that APP and Abeta, the major component of amyloid, bind the redox metal ion copper with high affinity and that these proteins are capable of reducing Cu(II), with the subsequent generation of reactive oxygen species. Thus, the ability of Abeta to bind and reduce Cu(II) (and Fe(III) in the case of Abeta) engenders a situation whereby Abeta may be chemically modified, and may explain many of the others oxidative modifications observed in and around amyloid plaques. Indeed, we have shown that in the presence of redox active metals, Abeta forms sodium dodecyl sulphate-resistant polymers like those extracted from the AD brain. Thus, the recently reported uptake of metal ions by Abeta deposits may result in oxidative modifications that lead to the formation of Abeta polymers and the progressive deposition of Abeta into hard core amyloid plaques. It is possible that similar reactions also drive the deposition of other cuproproteins that deposit in neurodegenerative diseases. This study is designed to further characterize metal ion binding to proteins known to deposit within the brain, such as alpha- synuclein in Parkinson s disease, prion protein in prion diseases and Abeta in Alzheimer s disease. In addition, using standard analytical methods, we will test whether metal ions induce the aggregation and/or polymerization of alpha-synuclein and PrP. Finally, we will attempt to locate chemical modifications in these proteins that might explain the mechanism of polymerization. These data will be important in determining the mechanism behind neuronal protein precipitation and may yield insights into how to prevent their deposition in vivo.