Genetic etiology of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症的遗传病因学

• 批准号: 10005767
• 负责人: Bryan Traynor
• 金额: $ 116.85万
• 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/10005767
• 关键词: Accounting; Age; Aging; Alzheimer' s Disease; American; Amyotrophic Lateral Sclerosis; Base Pairing; C9ORF72; Canada; Cholesterol; Chromosomes, Human, Pair 9; Clinical; Collaborations; Cost Savings; DNA; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Elderly; European; Familial Amyotrophic Lateral Sclerosis; Family; Frontotemporal Dementia; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genotype; Germany; Health Care Costs; Israel; Italy; Journals; Laboratories; Light; Link; Massachusetts; Medicine; Molecular; Motor; Mutation; Myasthenia Gravis; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; New England; Paper; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patients; Population; Publications; Publishing; Randomized; Recording of previous events; Research; Research Subjects; Respiratory Failure; Risk Factors; Role; Sampling; Technology; Therapeutic Agents; Time; United States National Institutes of Health; Universities; Western World; age related; clinical Diagnosis; cohort; disease diagnosis; effective therapy; frontotemporal lobar dementia-amyotrophic lateral sclerosis; gene discovery; gene therapy; genetic variant; genome sequencing; genome wide association study; innovation; motor neuron degeneration; nervous system disorder; neurogenetics; next generation sequencing; novel therapeutics; recruit; 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. In 2011, the Neuromuscular Diseases Research Section (NDRS), 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 patients clinically diagnosed with Alzheimer's disease. 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. In 2018, we published the largest genome-wide association study of ALS in collaboration with John Landers of the University of Massachusetts. This effort identified mutations in the KIF5A gene as a cause of familial and sporadic disease. In 2019, we published a data-driven Mendelian randomization paper in which we identified elevated cholesterol as a risk factor for ALS. Ongoing projects in the laboratory include: (1) genome 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) Genetic studies of myasthenia gravis, a common form of neuromuscular disease in the general population. 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.

肌萎缩性侧索硬化症（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是西方世界中第三大常见的神经退行性疾病，目前尚无有效的疗法。额颞痴呆（FTD）是65岁以下人群中最常见的痴呆形式。长期以来，这两种临床上不同的神经系统疾病之间的重叠已被认识到，但是该交叉点的分子基础尚不清楚。 2011年，美国国家衰老研究所的神经遗传学实验室的一部分神经肌肉疾病研究科（NDRS）确定了ALS和FTD的主要遗传原因。为此，Traynor博士（NDRU的负责人）组织了一个全球的财团，将以前曾是竞争对手集中精力努力识别该基因的竞争对手组合在一起。 NIH可用的下一代测序技术使这成为可能。这种创新的方法奏效了，他的小组在2011年9月在神经元期间发表了染色体9连接的ALS/FTD的原因。在这些情况下，该疾病是由六个基对DNA的六个基对DNA引起的，该疾病在病理上一遍又一遍地重复，多达几千次。这种所谓的大型六核苷酸重复破坏了位于9号染色体上的C9ORF72基因。这是迄今为止确定的ALS和FTD的最常见遗传原因，约占欧洲和北美人口中ALS和FTD的所有家族案例的大约40％。此外，Traynors Group博士表明，这种突变是偶发发生的ALS和FTD病例的8％是缺乏家族病史的情况。这代表了这些疾病的零星形式首次确定共同的遗传原因。在《新英格兰医学杂志》上的另一份出版物中，他们还表明，相同的大型六核苷酸重复扩张是1％的临床诊断患有阿尔茨海默氏病的患者。每年减少的AD案例数量减少1％，约占医疗保健成本约10亿美元。 C9ORF72六核苷酸重复扩张的发现是我们对神经退行性疾病的理解。它已经极大地影响了这些疾病的诊断，研究和感知，并在两种临床上不同的疾病ALS和FTD之间提供了机械联系。它还为旨在改善疾病的基因疗法工作提供了一个独特的治疗靶标，并且此类努力已经在进行中。 2018年，我们与马萨诸塞大学的约翰·兰德斯（John Landers）合作发布了最大的全基因组协会研究。这项工作将KIF5A基因中的突变确定为家族性和零星疾病的原因。 2019年，我们发表了一份数据驱动的孟德尔随机论文，其中我们将升高的胆固醇视为ALS的危险因素。 实验室中正在进行的项目包括：（1）对其他家族性ALS样品进行基因组测序，以寻找运动神经元变性的原因。这些案例的DNA是从我们的合作者Adriano Chio（意大利），迈克尔·森特纳（Michael Sendtner），德国（Dermany），埃卡特琳娜·罗加娃（Ekaterina Rogaeva）（加拿大）和维维安·德里（Vivian Drory）（以色列）获得的，以及我们自己在当地和全国范围内招募主题的努力； （2）肌无力的遗传研究，这是普通人群中神经肌肉疾病的一种常见形式。 总而言之，当年在使用下一代测序技术中确定在ALS发病机理中重要的遗传变异方面非常成功。这些研究中的每一个都采用了大量研究对象，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。通过了解晚期发作的运动神经变性的基础机制，我们还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迁移率下降。