Identifying Liver Proteins that Decrease Mutant SOD1 Misfolding and Decrease SOD1

描述（由申请人提供）：突变体SOD 1与肌萎缩性侧索硬化症的家族性形式有关，肌萎缩性侧索硬化症是一种以脊髓中运动神经元的进行性丧失为特征的疾病，伴随虚弱、骨骼肌萎缩、运动功能丧失、瘫痪，并最终在诊断后3-5年内死于呼吸衰竭。SOD 1是一种普遍存在的负责清除氧自由基的蛋白质;因此，这种广泛表达的蛋白质的突变如何导致组织特异性毒性仍然是一个谜。一种假说认为，SOD 1的毒性是由其错误折叠和聚集引起的。对这一假设的支持源于突变SOD 1在脑和脊髓中形成聚集体，但不在肝脏或其他非中枢神经系统组织中形成聚集体的观察。我们现在正在使用各种生物化学技术来表征来自肝脏的蛋白质，这些蛋白质显然对SOD 1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，最终目标是一种新的患者治疗方法。 公共卫生相关性：这项研究的目的是确定肝脏中的一种或多种蛋白质，这些蛋白质导致SOD 1蛋白的正常处理，尽管发生了突变。脊髓神经元退化，并有证据错误折叠，聚集的SOD 1。本研究的最终目的是修改已鉴定的通路或添加已鉴定的蛋白质，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。这可能会为ALS和其他神经退行性疾病带来新的治疗方法。

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.