REDOX METAL IONS AND NEURONAL PROTEIN DEPOSITION

氧化还原金属离子和神经元蛋白沉积

• 批准号: 2859119
• 负责人: Craig S Atwood
• 金额: $ 8.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2859119
• 关键词: aging; alpha synuclein; amyloid proteins; cations; copper; iron; metal complex; metalloproteins; polymerization; prions; zinc

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.

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）的共同神经病理学特征是存在与脑内蛋白质沉积物相关的氧化应激的局灶性标志物。 与这些疾病共同的是许多铜蛋白，如淀粉样蛋白前体（APP）、朊病毒蛋白、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，我们报道了APP和Abeta，淀粉样蛋白的主要成分，结合氧化还原金属离子铜具有高亲和力，这些蛋白质能够减少铜（II），与随后产生的活性氧。 因此，Abeta结合和还原Cu（II）（和Fe（III）在Abeta的情况下）的能力产生了Abeta可能被化学修饰的情况，并且可以解释在淀粉样蛋白斑块中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，Abeta形成十二烷基硫酸钠抗性聚合物，就像从AD大脑中提取的那些聚合物一样。 因此，最近报道的Abeta沉积物对金属离子的吸收可能导致氧化修饰，导致Abeta聚合物的形成和Abeta逐渐沉积到硬核淀粉样斑块中。 类似的反应也可能驱动在神经退行性疾病中存款的其他铜蛋白的沉积。本研究旨在进一步表征金属离子与已知在脑内存款的蛋白质的结合，例如帕金森氏病中的α-突触核蛋白，朊病毒疾病中的朊病毒蛋白和阿尔茨海默氏病中的Abeta。 此外，使用标准分析方法，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，我们将试图定位这些蛋白质中可能解释聚合机制的化学修饰。 这些数据将是重要的，在确定神经元蛋白沉淀背后的机制，并可能产生洞察如何防止其在体内沉积。