Structural and Biophysical Properties of Oligermeric SOD1

由于铜锌超氧化物歧化酶（SO01）突变与家族性ALS （FALS）之间的联系

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.