The Role of the Terminal Complement Pathway in ALS

描述(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，导致皮质、脑干和脊髓运动神经元退化，导致进行性瘫痪并最终死亡。ALS的发生主要是散发性的(SALS)，但大约5%到10%的病例是家族性的，与几个基因中的一个突变有关，包括铜、锌、SOD-1、Alsin、Senataxin、TDP-43和fus/TLS。目前还没有预防或治愈肌萎缩侧索硬化症的方法，唯一被批准的治疗方法是利鲁唑，只延长了几个月的生存期，被认为是无效的。鉴于缺乏有效的治疗方法，以及估计罹患SAL的终生风险从1/400到1/1000不等，因此对疾病生物标记物和疾病修饰疗法的需求至关重要。神经炎症作为一种参与ALS运动神经元丢失的机制而受到关注，这在很大程度上是因为人们认识到免疫介导的因素对其他神经退行性疾病的贡献，包括多发性硬化症、阿尔茨海默氏症和帕金森氏病。补体系统是先天免疫系统的主要组成部分，在大多数中枢神经系统疾病和感染中，补体系统与其他炎症介质一起推动神经炎症。越来越多的证据表明，补体有助于肌萎缩侧索硬化症的神经退变。一些研究已经发现ALS患者脊髓中存在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的升高。此外，在ALS的啮齿动物模型中，在小鼠ALS的前期和症状阶段，运动神经元和神经肌肉接头的补体基因表达和补体沉积发生了变化。然而，补体在肌萎缩侧索硬化症的发生和发展中的作用仍不明确。我们采用了一种系统的方法，通过将SOD1G93A转基因小鼠与补体系统的两个中心蛋白C3或C5缺失的小鼠杂交，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，表明膜攻击复合体有助于ALS的神经退变。此外，我们发现在SOD1G93A小鼠中，雌性C5+/-x SOD1G93A小鼠的存活时间显著长于各自的性别，这一观察结果与雌性小鼠C5水平的降低有关。我们假设C5在ALS的发展和进展中发挥核心作用，并将通过比较SOD1G93A TG和SOD1G93A缺乏C3、C5、C5aR或C9的两种性别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肌萎缩侧索硬化症中的作用的新信息，并可能提供新的治疗方向。

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.