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

生命的基本单位，细胞，将食物和氧气转化为能量来产生蛋白质，蛋白质是细胞构建和运作所必需的成分。蛋白质的不同作用和它们的水平决定了健康或疾病。提供组成数千种蛋白质的信息的蓝图被安置在细胞中心(核)的基因形式下。从蓝图中复制的小信使分子被运出细胞核，在称为核糖体的专门工厂中充当制造每种蛋白质的单独说明手册。名为C9ORF72的基因中短重复基序的扩展是最常见的变化，会导致成人两种无法治愈的致命神经退行性疾病，肌萎缩侧索硬化症(ALS)和额颞痴呆(FTD)。在英国，任何时候都有大约10,000人患有肌萎缩侧索硬化症和功能障碍。大脑前部和侧部神经细胞的进行性损伤和死亡会引起FTD患者个性和行为的特征性变化。另一方面，在肌萎缩侧索硬化症中观察到的进行性瘫痪是由于运动神经的死亡，这些运动神经通过从大脑和脊髓向肌肉传递信号来控制运动。部分ALS患者也会发生FTD，相反，许多FTD患者最终会发展为ALS。虽然目前还没有治疗FTD的方法，但目前ALS患者的治疗标准--利鲁唑--只能略微延长生存期。因此，确定治疗目标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是导致神经细胞死亡的一个重要机制，涉及产生异常的C9ORF72信使，引导有毒蛋白质的构建，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患者的存活率，但它不能提供治愈，也不能防止异常生物分子的产生。我们最近发现了一些在生产C9ORF72重复蛋白的工厂服务的专门分子。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脏细胞模型中得出的。我们现在想使用果蝇动物模型和用尖端科学技术从C9ORF72-ALS/FTD患者的皮肤中提取人类神经细胞来测试这一突破性发现是否适用于与疾病相关的C9ORF72-ALS/FTD模型。在这个项目中，我们还想研究降低特化分子水平对其他正常蛋白质生产的全局影响，并测试它们是否直接参与了异常重复蛋白的制造。综上所述，这项研究将测试一种新的概念，在不久的将来可能治疗C9ORF72连锁的ALS/FTD患者。这一新策略也可能对其他疾病有用，包括脆性X相关震颤/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，这一最先进的科学将带来鼓舞人心的交流、演示和出版物，这将使学术界、普通公众、当地学校、高等教育部门受益，从长远来看，还可能使医疗保健专业人员和制药行业受益。

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.