Identifying Liver Proteins that Decrease Mutant SOD1 Misfolding and Decrease SOD1

鉴定可减少突变 SOD1 错误折叠并减少 SOD1 的肝脏蛋白

• 批准号: 8129435
• 负责人: TIMOTHY M. MILLER
• 金额: $ 18.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129435
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Animals; Anions; Antibodies; Atrophic; Back; Bacteria; Biochemical; Biological Assay; Brain; Cell Culture Techniques; Cells; Cessation of life; Cultured Cells; Cytosol; Data; Diagnosis; Disease; Functional disorder; Future; Goals; Grant; Human; Lead; Liver; Mass Spectrum Analysis; Membrane; Methods; Molecular Sieve Chromatography; Motor; Motor Neurons; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Paralysed; Pathway interactions; Patients; Proteins; Pyroxylin; Rattus; Recombinant Proteins; Respiratory Failure; Rodent; Signal Transduction; Skeletal Muscle; Source; Specificity; Spinal; Spinal Cord; System; Techniques; Therapeutic; Tissues; Toxic effect; Translating; Work; disease phenotype; free radical oxygen; in vitro Assay; mutant; neurotoxicity; novel; prevent; protective effect; protein misfolding; public health relevance; research study; stem

DESCRIPTION (provided by applicant): Mutant SOD1 has been implicated in familial forms of amyotrophic lateral sclerosis, a disease marked by the progressive loss of motor neurons in the spinal cord, with concomitant weakness, atrophy of skeletal muscles, loss of motor function, paralysis, and eventual death from respiratory failure in 3-5 years post diagnosis. SOD1 is a ubiquitous protein responsible for scavenging oxygen free radicals; thus, how mutations in such a widely expressed protein result in tissue specific toxicity remains a mystery. One hypothesis asserts that the toxicity of SOD1 results from its misfolding and aggregation. Support for this hypothesis stems from the observation that mutant SOD1 forms aggregates in brain and spinal cord, but not in the liver or other non central nervous system tissues. We are now using a variety of biochemical techniques to characterize proteins from liver that apparently have a protective effect on SOD1 misfolding. Future experiments include the purification, identification, and characterization of the liver factor, with the ultimate goal of a novel patient therapy. PUBLIC HEALTH RELEVANCE: The goal of this study is to identify the protein or proteins in the liver that lead to normal handling of SOD1 protein despite the mutations. Spinal cord neurons degenerate and have evidence of misfolded, aggregated SOD1. The ultimate goal of this study is to modify the pathway identified or add back the proteins identified to enhance the ability of spinal cord to clear/handle the misfolded protein and thus decrease the neurotoxicity. This could lead to a novel treatment for ALS and, perhaps, other neurodegenerative diseases.

描述（由申请人提供）：突变SOD1与家族性肌萎缩性侧索硬化症有关，这种疾病以脊髓中运动神经元的进行性丧失，伴随性无力，骨骼肌肉的萎缩，骨骼肌肉的萎缩，运动瘫痪，瘫痪，瘫痪，瘫痪，最终死亡，以及3-5岁诊断的呼吸衰竭。 SOD1是一种无处不在的蛋白质，负责清除氧气自由基。因此，这种广泛表达的蛋白质中的突变如何导致组织特异性毒性仍然是一个谜。一个假设断言SOD1的毒性是由于其错误折叠和聚集而引起的。对这一假设的支持源于观察到突变SOD1在脑和脊髓中形成聚集体，但在肝或其他非中枢神经系统组织中不存在。现在，我们正在使用各种生化技术来表征肝脏的蛋白质，显然对SOD1错误折叠具有保护作用。未来的实验包括肝脏因子的纯化，鉴定和表征，这是一种新的患者疗法的最终目标。 公共卫生相关性：这项研究的目的是鉴定肝脏中蛋白质或蛋白质的蛋白质，尽管突变发生了，但导致SOD1蛋白正常处理。脊髓神经元退化，并具有错误折叠的骨料骨状SOD1的证据。这项研究的最终目标是修改识别的途径或添加鉴定的蛋白质，以增强脊髓清除/处理错误折叠蛋白的能力，从而降低神经毒性。这可能会导致对ALS以及其他神经退行性疾病的新型治疗方法。