Genetic etiology of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症的遗传病因学

• 批准号: 8736652
• 负责人: Bryan Traynor
• 金额: $ 56.32万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736652
• 关键词: Accounting; Age; Aging; Alzheimer' s Disease; American; Amyotrophic Lateral Sclerosis; Base Pairing; C9ORF72; Canada; Chromosomes, Human, Pair 9; Cost Savings; DNA; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Elderly; European; Familial Amyotrophic Lateral Sclerosis; Family; Finland; Frontotemporal Dementia; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Germany; Health Care Costs; International; Israel; Italy; Journals; Laboratories; Light; Link; London; Medicine; Molecular; Motor; Mutation; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; New England; Paralysed; Pathogenesis; Pathway interactions; Population; Publications; Publishing; Recording of previous events; Recruitment Activity; Research; Research Subjects; Respiratory Failure; Role; Sampling; Technology; Therapeutic Agents; Time; United States National Institutes of Health; Universities; Western World; age related; base; cohort; college; disease diagnosis; effective therapy; exome sequencing; gene discovery; gene therapy; genetic variant; genome wide association study; innovation; interest; motor neuron degeneration; nervous system disorder; neurogenetics; next generation sequencing; novel therapeutics; therapeutic target; working group

Amyotrophic lateral sclerosis (ALS; Lou Gehrigs disease) is a fatal neurodegenerative disorder that leads to rapidly progressive paralysis and respiratory failure. ALS is the third most common neurodegenerative disease in the Western World, and there are currently no effective therapies. Frontotemporal dementia (FTD) is the most common form of dementia in the population under the age of 65. An overlap between these two clinically distinct neurological diseases has long been recognized, but the molecular basis of this intersection was unknown. Recently, the Neuromuscular Diseases Research Unit (NDRU), a part of the Laboratory of Neurogenetics at the National Institute on Aging, identified the major genetic cause of both ALS and FTD. To do this, Dr. Traynor (chief of NDRU) organized a worldwide consortium, bringing together groups that had previously been competitors to focus their efforts towards identifying this gene. This was made possible by the next generation sequencing technologies available at the NIH. This innovative approach worked, and his group published the cause of chromosome 9-linked ALS/FTD in the journal Neuron in September 2011. In these cases, the disease is caused by a six base pair segment of DNA that is pathologically repeated over and over again, up to several thousand times. This so-called large hexanucleotide repeat disrupts the C9ORF72 gene located on chromosome 9. This is the most common genetic cause of both ALS and FTD identified to date, accounting for approximately 40% of all familial cases of ALS and FTD in European and North American populations. Further, Dr. Traynors group has shown that this mutation underlies about 8% of cases of sporadically occurring ALS and FTD that lack a family history. This represents the first time that a common genetic cause has been identified for the sporadic form of these diseases. In a separate publication in The New England Journal of Medicine, they have also shown that the same large hexanucleotide repeat expansion underlies 1% of Alzheimers disease cases. A one percent reduction in the number of AD cases would represent approximately $1 billion in healthcare cost savings annually. The discovery of the C9ORF72 hexanucleotide repeat expansion is a landmark discovery in our understanding of neurodegenerative disease. It has already greatly effected how these diseases are diagnosed, investigated and perceived, and provides a mechanistic link between two clinically distinct disorders, ALS and FTD. It also provides a distinct therapeutic target for gene therapy efforts aimed at ameliorating the disease, and such efforts are already well underway. Ongoing projects in the laboratory include: (1) exome sequencing of additional familial ALS samples to look for causative genes underlying motor neuron degeneration. DNA for these cases were obtained from our collaborators, Adriano Chio (Italy), Michael Sendtner (Germany), Ekaterina Rogaeva (Canada), and Vivian Drory (Israel), as well as our own efforts to recruit subjects locally and nationally; (2) Large scale genome-wide association study. To achieve this, we have reached out to other laboratories interested in studying this locus, and formed an international consortium involving the University College London, the University of Turin, and the University of Helsinki in Finland. In summary, the current year has been incredibly successful in identifying genetic variants important in the pathogenesis of ALS using next generation sequencing technologies. Each of these studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA. By understanding the cellular mechanisms underlying late-onset motor neurodegeneration, we also hope to shed light on the role of aging in the CNS and in age-related decline in mobility.

肌萎缩侧索硬化症（ALS; Lou Gehrigs病）是一种致命的神经退行性疾病，可导致快速进行性瘫痪和呼吸衰竭。ALS是西方世界第三常见的神经退行性疾病，目前尚无有效的治疗方法。额颞叶痴呆（FTD）是65岁以下人群中最常见的痴呆形式。这两种临床上不同的神经系统疾病之间的重叠早已被认识到，但这种交叉的分子基础是未知的。 最近，神经肌肉疾病研究单位（NDRU），国家老龄化研究所神经遗传学实验室的一部分，确定了ALS和FTD的主要遗传原因。为了做到这一点，Traynor博士（NDRU的负责人）组织了一个全球性的财团，将以前是竞争对手的团体聚集在一起，集中精力鉴定这种基因。这是由NIH提供的下一代测序技术实现的。这种创新的方法奏效了，他的团队于2011年9月在Neuron杂志上发表了9号染色体连锁ALS/FTD的原因。在这些情况下，这种疾病是由一个六碱基对的DNA片段引起的，它在病理上反复重复，多达几千次。这种所谓的大六核苷酸重复序列破坏了位于9号染色体上的C9 ORF 72基因。这是迄今为止发现的ALS和FTD最常见的遗传原因，约占欧洲和北美人群中ALS和FTD所有家族性病例的40%。此外，Traynors博士的研究小组已经表明，这种突变是大约8%缺乏家族史的偶发性ALS和FTD病例的基础。这是第一次发现这些疾病散发形式的共同遗传原因。在《新英格兰医学杂志》的另一篇文章中，他们还表明，1%的老年痴呆症病例是由同样大的六核苷酸重复扩增引起的。AD病例数量减少1%将意味着每年节省约10亿美元的医疗费用。 C9 ORF 72六核苷酸重复扩增的发现是我们理解神经退行性疾病的里程碑式发现。它已经极大地影响了这些疾病的诊断，调查和感知，并提供了两个临床不同的疾病，ALS和FTD之间的机械联系。它还为旨在改善疾病的基因治疗工作提供了一个独特的治疗靶点，这种努力已经在进行中。 实验室正在进行的项目包括：（1）额外的家族性ALS样本的外显子组测序，以寻找运动神经元变性的致病基因。这些病例的DNA来自我们的合作者Adriano Chio（意大利）、Michael Sendtner（德国）、Ekaterina Rogaeva（加拿大）和Vivian Drory（以色列），以及我们自己在当地和全国招募受试者的努力;（2）大规模全基因组关联研究。为了实现这一目标，我们已经联系了其他有兴趣研究这一位点的实验室，并成立了一个国际联盟，包括伦敦大学学院、都灵大学和芬兰的赫尔辛基大学。 总之，今年在使用下一代测序技术鉴定ALS发病机制中重要的遗传变异方面取得了令人难以置信的成功。这些研究中的每一项都采用了大量的研究对象，并利用了NIA神经遗传学实验室内可用的测序和基因分型设施。通过了解迟发性运动神经退行性变的细胞机制，我们也希望阐明衰老在中枢神经系统中的作用以及与年龄相关的运动能力下降。