Modeling the progression of SOD1-linked motor neuron disease

模拟 SOD1 相关运动神经元疾病的进展

• 批准号: 8942269
• 负责人: DAVID R BORCHELT
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8942269
• 关键词: Address; Affect; Age; Age-Months; Amino Acids; Amyotrophic Lateral Sclerosis; Animals; Back; Biological; Biological Models; Cell Culture Techniques; Cells; Clinical; Cuprozinc Superoxide Dismutase; Data; Data Set; Disease; Disease Progression; Evolution; Familial Amyotrophic Lateral Sclerosis; Follow-Up Studies; Frequencies; Genotype; Goals; Health; Incidence; Individual; Injection of therapeutic agent; Investigation; Life; Link; Mediating; Modeling; Molecular Conformation; Motor; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Nervous system structure; Neuraxis; Newborn Infant; Organism; Outcome; Paralysed; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Predisposition; Preparation; Prion Diseases; Prions; Property; Proteins; Publishing; Recording of previous events; Research Design; Respiration; Source; Speed; Spinal; Spinal Cord; Surveys; Symptoms; Testing; Therapeutic; Tissues; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; Variant; Work; aged; base; cohort; illness length; in vivo; mouse model; mutant; postnatal; prion-like; protein misfolding; research study; sciatic nerve; superoxide dismutase 1; transmission process

DESCRIPTION (provided by applicant): Cu-Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (fALS) is an extremely heterogeneous disease phenotypically with diverse clinical symptoms that can originate in upper or lower motor neurons and with a wide range of disease durations, from as short as a year to as long as 20 years. The duration of disease is largely a function of the speed with which symptoms spread along the neuraxis until motor neurons involved in respiration become affected. The question of how the disease seems to spread is one of the major unanswered questions in the study of ALS. Over the past few years, there has been increasing evidence that one mechanism by which the disease spreads may involve a prion-like propagation of a toxic misfolded protein from cell to cell along anatomically connected pathways of the CNS. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3-11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A→G85R-YFP mice back into newborn G85R-YFP mice, induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly, regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Although these preliminary findings are very exciting, we recognize that our studies to date are underpowered and we cannot fully assess the ease with which SOD1-linked motor neuron disease (MND) can be transmitted between animals without a much larger effort. Aims 1 and 2 propose such an effort to better understand genotype/phenotype interactions in transmitting MND in these models. We also have very exciting evidence that we might be able to create a model in which we could initiate disease focally, by injecting the "infectious" tissue homogenates from paralyzed mice in to the sciatic nerves of vulnerable transgenic models. However, again, our preliminary data is limited and much larger effort is required. Aim 3 proposes such an effort. Collectively, our studies are designed to better establish the biological relevance of SOD1-MND transmissibility and to build model systems that would enable investigations into the mechanisms of disease progression.

描述（由申请人提供）：铜锌超氧化物歧化酶 1 (SOD1) 相关的家族性肌萎缩侧索硬化症 (fALS) 是一种表型极其异质的疾病，具有多种临床症状，可起源于上运动神经元或下运动神经元，并且具有多种症状疾病持续时间，短至一年，长至 20 年。疾病持续时间很大程度上取决于症状沿神经轴传播的速度。参与呼吸的运动神经元受到影响，这种疾病如何传播是 ALS 研究中尚未解决的主要问题之一，越来越多的证据表明该疾病可能通过一种机制传播。涉及有毒错误折叠蛋白质沿着中枢神经系统的解剖学连接通路在细胞之间进行类似朊病毒的传播。这些蛋白质可以在细胞之间传播有毒构象，也可以通过实验在个体生物体之间传播疾病。 (MND) 可以传播，我们将表达突变型超氧化物歧化酶 1（SOD1-G93A 和 G37R）的瘫痪小鼠制备的脊髓匀浆注射到遗传上易受伤害的 SOD1 转基因小鼠的脊髓中，从我们测试的各种模型中，出现了一个如下所示。来自瘫痪 G93A 小鼠的组织匀浆在 10 只表达低水平 G85R-SOD1 融合黄色的小鼠中诱导了 MND。荧光蛋白（G85R-YFP 小鼠）3-11 个月，并产生广泛的脊柱包涵体病理学。重要的是，将来自 G93A→G85R-YFP 小鼠的匀浆第二次传回新生 G85R-YFP 小鼠，在 4 只小鼠中诱导了 4 只疾病。无论注射的受体转基因动物的品系如何，来自表达 G37R 变体的瘫痪小鼠的匀浆均属于传播不良的组，这一发现提示。尽管这些初步发现非常令人兴奋，但我们认识到我们迄今为止的研究力度不足，而且我们无法完全评估 SOD1 相关运动神经元疾病 (MND) 传播的难易程度。目标 1 和 2 提出了这样的努力，以更好地理解在这些模型中传播 MND 的基因型/表型相互作用。可能引发疾病重点是，通过将来自瘫痪小鼠的“感染性”组织匀浆注射到易受攻击的转基因模型的坐骨神经中。然而，我们的初步数据仍然有限，并且我们的研究总体上需要付出更大的努力。旨在更好地建立 SOD1-MND 传播性的生物学相关性，并建立模型系统来研究疾病进展的机制。