The Role of the Terminal Complement Pathway in ALS

终末补体通路在 ALS 中的作用

• 批准号: 8511495
• 负责人: Scott R BARNUM
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511495
• 关键词: Address; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Attention; Behavior; Biological Markers; Body Weight decreased; Brain Stem; C5a anaphylatoxin receptor; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Classical Complement Pathway; Clinical; Complement; Complement 5a; Complement Activation; Complement Membrane Attack Complex; Deposition; Development; Disease; Female; Gender; Gene Expression; Gene Mutation; Genes; Immune; Immune system; Infection; Inflammation; Inflammation Mediators; Inflammatory; Lead; Mediating; Motor Neuron Disease; Motor Neurons; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Paralysed; Parkinson Disease; Pathway interactions; Patients; Peptides; Phenotype; Play; Primary Lateral Sclerosis; Proteins; Rattus; Research Personnel; Riluzole; Rodent Model; Role; Serum; Spinal Cord; Staging; Testing; Time; Transgenic Mice; Transgenic Organisms; arm; base; complement C5b; complement pathway; complement system; effective therapy; grasp; immunopathology; inhibitor/antagonist; lifetime risk; male; motor neuron degeneration; neuroinflammation; neuron loss; novel therapeutics; prophylactic; protein TDP-43; public health relevance

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that leads to degeneration of motor neurons in the cortex, brainstem and spinal cord resulting in progressive paralysis and ultimately death. The occurrence of ALS is largely sporadic (SALS), however approximately five to ten percent of cases are familial, associated with mutations in one of several genes including Cu,Zn SOD-1, Alsin, Senataxin, TDP-43 and FUS/TLS. There is currently no prophylactic therapy or cure for ALS and the only approved treatment, riluzole, extends survival only a few months and is considered ineffective. Given the lack of effective therapies and the estimated lifetime risk of developing SALS ranging from 1 in 400 to 1 in 1000, the need for disease biomarkers and disease-modifying therapies is critical. Neuroinflammation has received attention as a mechanism that participates in motor neuron loss in ALS, due in large part to the recognition of immune-mediated contributions to other neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease. The complement system, a major arm of the innate immune system, drives neuroinflammation along with other inflammatory mediators in most, if not all, central nervous system diseases and infections. There is growing evidence that complement contributes to neurodegeneration in ALS. Several studies have found evidence of complement activation and deposition in the spinal cord of ALS patients as well as elevated levels of complement activation fragments in cerebrospinal fluid (CSF) or serum. In addition, rodent models of ALS, have shown changes in complement gene expression and complement deposition in motor neurons and neuromuscular junctions in pre- and symptomatic stages of murine ALS. Nevertheless, the role of complement in the development and progression of ALS remains ill-defined. We have taken a systematic approach to address the role of complement in murine ALS by crossing SOD1G93A transgenic mice with mice deficient in C3 or C5, the two central proteins of the complement system. We observed a time-dependent deposition of C9 in the spinal cords of SOD1G93A mice suggesting that the membrane attack complex contributes to neurodegeneration in ALS. Furthermore, we found that female C5+/- x SOD1G93A mice survived significantly longer than the respective genders in SOD1G93A mice, an observation that correlates with the reduced C5 levels in female mice. We hypothesize that C5 plays a central role in the development and progression of ALS and will address this hypothesis by comparing the clinical and histological ALS phenotypes of both genders of mice that are SOD1G93A tg and deficient in C3, C5, C5aR or C9 to SOD1G93A mice. These studies will provide new information regarding the role of complement in ALS and potentially new therapeutic directions.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种进行性运动神经元疾病，导致皮层、脑干​​和脊髓中的运动神经元变性，导致进行性瘫痪并最终死亡。 ALS 的发生很大程度上是散发性的 (SALS)，但大约 5% 到 10% 的病例是家族性的，与 Cu,Zn SOD-1、Alsin、Senataxin、TDP-43 和 FUS/TLS 等几个基因之一的突变有关。目前 ALS 尚无预防性治疗或治愈方法，唯一获批的治疗方法利鲁唑只能延长几个月的生存期，并且被认为是无效的。鉴于缺乏有效的治疗方法，并且估计终生发生 SALS 的风险为四百分之一到千分之一，因此对疾病生物标志物和疾病缓解疗法的需求至关重要。神经炎症作为参与 ALS 运动神经元丧失的机制而受到关注，这在很大程度上是由于认识到免疫介导对其他神经退行性疾病（包括多发性硬化症、阿尔茨海默病和帕金森病）的贡献。补体系统是先天免疫系统的一个主要分支，在大多数（如果不是全部）中枢神经系统疾病和感染中与其他炎症介质一起驱动神经炎症。越来越多的证据表明补体会导致 ALS 的神经变性。多项研究发现 ALS 患者脊髓中补体激活和沉积的证据，以及脑脊液 (CSF) 或血清中补体激活片段水平升高的证据。此外，ALS 啮齿动物模型显示，在小鼠 ALS 前期和症状阶段，运动神经元和神经肌肉接头中补体基因表达和补体沉积发生变化。然而，补体在 ALS 发生和进展中的作用仍然不明确。我们采用系统方法，通过将 SOD1G93A 转基因小鼠与缺乏补体系统的两种核心蛋白 C3 或 C5 的小鼠杂交，来解决补体在小鼠 ALS 中的作用。我们观察到 C9 在 SOD1G93A 小鼠脊髓中的时间依赖性沉积，表明膜攻击复合物导致 ALS 中的神经变性。此外，我们发现雌性 C5+/- x SOD1G93A 小鼠的存活时间明显长于相应性别的 SOD1G93A 小鼠，这一观察结果与雌性小鼠中 C5 水平降低相关。我们假设 C5 在 ALS 的发生和进展中发挥核心作用，并将通过比较 SOD1G93A tg 和 C3、C5、C5aR 或 C9 缺陷的两性小鼠的临床和组织学 ALS 表型来解决这一假设。这些研究将提供有关补体在 ALS 中的作用以及潜在的新治疗方向的新信息。