Investigating mechanistic causes of C9ORF72-related amyotrophic lateral sclerosis (ALS).

细胞构成了人体的基本组成部分，将食物和氧气转化为能量以产生蛋白质。构成蛋白质的蓝图--DNA--位于细胞核中，细胞核是一个与周围隔室--细胞质分开的细胞中心，蛋白质在细胞质中组装成支持生命的机器。从蓝图复制的小信使种类（信使RNA）能够从细胞核进入细胞质，在细胞质中每个信使种类引导一种蛋白质的构建。蛋白质的数量和功能决定了包括运动神经元在内的细胞的存活或死亡。肌萎缩侧索硬化症（ALS）是一种致命的成人疾病，由连接肌肉与大脑和脊髓的神经细胞进行性死亡引起。这引起逐渐瘫痪和死亡，通常从症状发作起3-5年。目前还没有治愈的方法，唯一可用的药物是阿舒唑，效果不佳，只能延长大约3个月的生命。C9 ORF 72基因中重复序列的扩增是ALS患者DNA中最常见的改变。这种遗传改变会对数千种信使物种造成损害，导致细胞机器多个方面的潜在故障。然而，导致运动神经元损伤的真正元凶尚未找到，本项目旨在明确C9 ORF 72相关ALS中导致运动神经元损伤的各种潜在异常机制的作用及其病理作用模式，并帮助我们寻找对诊断和疾病监测有用的生物标志物。我们使用尖端的科学方法从健康和C9 ORF 72-ALS患者的皮肤细胞中产生神经细胞，并产生了其他细胞模型，用于单独研究一种潜在疾病机制的影响。使用这些模型，我们现在将能够进行旨在了解神经细胞的电/存活特性降低，信使种类的内容改变以及信使从细胞核进入细胞质的异常通道如何在疾病中发生的实验。在未来，我们希望从这项研究中更好地了解C9 ORF 72相关ALS的基本生物学机制，将允许开发新的神经保护治疗策略。

Cells constitute the basic building blocks of the human body converting food and oxygen into energy to produce proteins. The blueprint for making up proteins, the DNA, is housed in the nucleus, a cell centre separated from the surrounding compartment, the cytoplasm, where proteins are assembled into the machinery supporting life. Small messenger species (messenger RNAs) copied from the blueprint are able to pass from the nucleus into the cytoplasm where each guides the building of one protein. The quantity and function of proteins account for survival or death of cells including motor neurons. Amyotrophic lateral sclerosis (ALS) is a fatal adult disease caused by progressive death of nerve cells that connect muscles to the brain and the spinal cord. This provokes gradual paralysis and death usually 3-5 years from symptom onset. There is currently no cure and the only drug available, Riluzole, has modest effect prolonging life for only approximately 3 months. Expansion of a repeated sequence in the C9ORF72 gene is the commonest alteration found in the DNA of patients with ALS. This genetic alteration causes damage to thousands of messenger species resulting in the potential malfunction of multiple aspects of the cellular machinery. However, the actual culprit(s) causing motor neuron injury have not yet been found. This project aims to identify the contribution of each potential abnormal mechanism that causes motor neuron injury in C9ORF72-related ALS, their pathological mode of action, and will help us to find biomarkers useful in diagnosis and disease monitoring. We have used cutting-edge scientific methods to produce nerve cells from healthy and C9ORF72-ALS patients' skin cells and have generated other cell models engineered for studying individually the effects of one potential mechanism of disease at a time. Using these models, we will now be able to carry out experiments aimed at understanding how decreased electrical/survival properties of nerve cells, altered content of messenger species and abnormal passage of messengers from the nucleus into the cytoplasm, occur in disease. In the future, we expect that a better understanding of the basic biological mechanisms of C9ORF72-related ALS from this study will allow the development of novel strategies for neuroprotective therapy.