Structural and Biophysical Properties of Oligermeric SOD1

由于铜锌超氧化物歧化酶（SO 01）突变与家族性ALS（FALS）之间的联系， 大约10年前首次描述，世界各地的实验室都试图了解 突变使得SOD 1蛋白对运动神经元有毒。越来越多的证据表明这种有毒物质 来自突变SOD 1蛋白组装成更高级结构（可溶性寡聚体）的能力 和不溶性聚集体），以某种方式干扰神经元细胞机制。通过使用井 建立的单晶X射线衍射工具，我们最近观察到，五种不同的FALS突变体SOD 1 蛋白质可以形成“淀粉样”纤维，这在某种程度上让人想起在其他组织中看到的纤维类型。 神经退行性疾病，如阿尔茨海默病和帕金森病。致病性SOD 1蛋白 能够自我关联，但正常的未突变的SOD 1蛋白不能。本文中概述的实验 该项目旨在探索这些异常的病原性SOD 1-SOD 1相互作用，并帮助回答 以下问题：1）我们在X射线研究中观察到的自缔合模式是否是 致病性SO 01蛋白在活细胞中聚集？2)什么样的结构要素是毒性的决定因素 在病原性SOD 1？3)致病性SOD 1的氧化修饰在聚集中起作用吗？四、 致病性SOD 1的解离（单体）形式可能是聚集的原因吗？的答案 这些问题是设计旨在抑制聚集的治疗剂所需要的 过程

Since the link between mutations in copper-zinc superoxide dismutase (SO01) and familial ALS (FALS) was first described approximately 10 years ago, laboratories worldwide have sought to understand how the mutations render the SOD1 protein toxic to motor neurons. Evidence is accumulating that this toxic property comes from the ability of the mutant SOD1 proteins to assemble into higher order structures (soluble oligomers and insoluble aggregates) that somehow interfere with the neuronal cellular machinery. Using the well established tools of single crystal X-ray diffraction, we recently observed that five different FALS mutant SOD1 proteins can form "amyloid-like" fibers that are somewhat reminiscent of the types of fibers seen in other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The pathogenic SOD1 proteins are able to self-associate but the normal, unmutated SOD1 proteins cannot. The experiments outlined in this project are designed to probe these abnormal pathogenic SOD1-SOD1 interactions and to help answer the following questions: 1) Is the mode of self-association we observe in X-ray studies the basis for how the pathogenic SO01 proteins aggregate in living cells? 2) What structural elements are determinants of toxicity in pathogenic SOD1? 3) Does oxidative modification of pathogenic SOD1 play a role in aggregation? 4) Could a dissociated (monomeric) form of pathogenic SOD1 be responsible for aggregation? Answers to questions such as these are required for the design of therapeutic agents aimed inhibiting the aggregation process.