Novel therapeutic strategies to target RAN translation of pathological C9ORF72 repeat transcripts and associated neurodegeneration

细胞是生命的基本单位，它将食物和氧气转化为能量以产生蛋白质，而蛋白质是细胞构建和功能所不可缺少的成分。蛋白质的不同作用及其水平解释了健康或疾病。提供构成数千种蛋白质的信息的蓝图以基因的形式存在于细胞中心（细胞核）。从蓝图中复制的小信使分子被运送出细胞核，在那里它们作为单独的指导手册，在称为核糖体的专门工厂中制造每种蛋白质。C9ORF72基因中一个短重复基序的延伸是导致成人肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）这两种无法治愈和致命的神经退行性疾病的最常见的变化。在英国，任何时候都有大约10,000人患有ALS和FTD。大脑前部和侧部神经细胞的进行性损伤和死亡会引起FTD患者性格和行为的特征性变化。另一方面，在ALS中观察到的进行性瘫痪是由于通过从大脑和脊髓向肌肉传递信号来控制运动的运动神经死亡。一部分ALS患者也会发展为FTD，反之，许多FTD患者最终也会发展为ALS。虽然目前尚无治疗FTD的方法，但目前ALS患者的标准治疗方法利鲁唑只能略微延长生存期。因此，确定治疗靶点以治愈或减缓这些神经退行性疾病的进展是至关重要的。C9ORF72重复元件的大量延伸被认为导致神经细胞死亡的一个重要机制涉及异常C9ORF72信使的产生，这些信使引导有毒蛋白的构建，从而引发多种细胞损伤机制。虽然利鲁唑可能会适度增加C9ORF72相关ALS患者的生存，但它不能提供治愈，也不能阻止异常生物分子的产生。我们最近发现了一些在生产c9orf72重复蛋白的工厂中服务的特殊分子。我们还发现，减少它们的数量可以停止有毒蛋白质的制造，阻止细胞死亡。这些发现是在世界各地实验室常规使用的人类肾细胞模型中得出的。我们现在想要测试这一突破性发现是否适用于C9ORF72-ALS/FTD疾病相关模型，使用果蝇动物模型和采用尖端科学技术从C9ORF72-ALS/FTD患者皮肤中制造的人类神经细胞。在这个项目中，我们还想研究降低特化分子水平可能对其他正常蛋白质产生的整体影响，并测试它们是否直接参与异常重复蛋白质的制造。总之，这项研究将在不久的将来测试c9orf72相关ALS/FTD患者潜在治疗的新概念。这种新策略也可能对其他疾病有用，包括脆性x相关的震颤/共济失调综合征，阿尔茨海默病和某些形式的癌症。包括科学家和临床医生在内的几个研究人员合作社区将参与这项研究。此外，这种最先进的科学将带来鼓舞人心的交流、演讲和出版物，这将有利于学术界、公众、当地学校、第三产业，从长远来看，还可能有利于医疗保健专业人员和制药行业。

The basic units of life, cells, convert food and oxygen into energy to produce proteins, constituents indispensable to the building and functioning of cells. The diverse roles of proteins and their levels account for health or diseases. The blueprint providing the information for making up thousands of proteins is housed under the form of genes in the cell centre (nucleus). Small messenger molecules copied from the blueprint are transported out of the nucleus where they serve as individual instruction manuals for manufacturing each protein within specialized factories called ribosomes.Extensions of a short repeated motif in a gene called C9ORF72 are the most common changes causing two incurable and lethal neurodegenerative diseases in adults, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Approximately 10,000 individuals suffer from ALS and FTD at any time in the United Kingdom. Progressive injury and death of nerve cells in the front and side parts of the brain provokes characteristic changes in the personality and behaviour of patients suffering from FTD. On the other hand, the progressive paralysis observed in ALS is due to the death of motor nerves that control movements by transmitting signals from the brain and spinal cord to the muscles. A proportion of patients with ALS disease also develop FTD, and conversely, many patients with FTD will eventually develop ALS. Whilst no treatment is available for FTD, the current standard of care for ALS patients, riluzole, only marginally extends survival. The identification of therapeutic targets to cure or slow down the progression of these neurodegenerative diseases is therefore of paramount importance. A prominent mechanism by which large extensions of the C9ORF72 repeated elements are thought to cause death of nerve cells involves the production of aberrant C9ORF72 messengers guiding the building of toxic proteins that provoke multiple cellular damage mechanisms. Although riluzole might moderately increase the survival of patients with C9ORF72 related ALS, it does not provide a cure and does not prevent the production of abnormal biomolecules.We recently identified some of the specialized molecules serving in the factories where the C9ORF72-repeated proteins are produced. We also found that reducing their number can halt the manufacture of the toxic proteins and stops cells from dying. These findings were made in a human kidney cell model routinely used in laboratories around the world. We now want to test whether this groundbreaking discovery holds true in disease-relevant models of C9ORF72-ALS/FTD using a fruit fly animal model and human nerve cells made with cutting-edge scientific technologies from the skin of C9ORF72-ALS/FTD patients. In this project, we also want to study the global effects that reducing the levels of the specialized molecules may have on the production of the other normal proteins and test whether they are directly involved in the manufacture of the abnormal repeated proteins.In summary, this research will test a novel concept for a potential treatment of patients suffering with C9ORF72-linked ALS/FTD in the near future. This novel strategy could also potentially be useful for other diseases including Fragile X-associated Tremor/Ataxia syndrome, Alzheimer's disease and some forms of cancer. Several collaborating communities of researchers including scientists and clinicians will be involved with the research. Furthermore, this state-of-the-art science will lead to inspirational communications, presentations and publications that will benefit the academic community, the general public, local schools, the tertiary sector and potentially in the longer term, healthcare professionals and the pharmaceutical industry.