Genetic etiology of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症(ALS；Lou Gehrig病)是一种致命的神经退行性疾病，导致快速进行性瘫痪和呼吸衰竭。肌萎缩侧索硬化症是西方世界第三常见的神经退行性疾病，目前还没有有效的治疗方法。额颞性痴呆(FTD)是65岁以下人群中最常见的痴呆症形式。这两种临床上截然不同的神经疾病之间的重叠早已被认识到，但这种交叉的分子基础尚不清楚。 2011年，国家老龄研究所神经遗传学实验室的神经肌肉疾病研究部(NDRS)确定了ALS和FTD的主要遗传原因。为了做到这一点，特雷诺博士(NDRU的负责人)组织了一个世界性的联盟，将以前是竞争对手的团队聚集在一起，集中精力识别这种基因。这是由美国国立卫生研究院提供的下一代测序技术实现的。这种创新的方法奏效了，他的团队在2011年9月的《神经元》杂志上发表了9号染色体相关的ALS/FTD的原因。在这些病例中，这种疾病是由一段六个碱基对的DNA引起的，这种DNA在病理上反复重复，多达数千次。这个所谓的大六核苷酸重复序列破坏了位于9号染色体上的C9ORF72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ALS和FTD家族性病例的40%。此外，特雷诺博士的团队还发现，在没有家族病史的零星发生的ALS和FTD病例中，约有8%是由这种突变引起的。这是首次为这些疾病的零星形式确定共同的遗传原因。在发表在《新英格兰医学杂志》的另一篇文章中，他们还表明，在临床诊断为阿尔茨海默病的患者中，1%的患者存在同样的大六核苷酸重复扩增。AD病例数量每减少1%，每年将节省约10亿美元的医疗成本。 C9ORF72六核苷酸重复序列扩增的发现是我们对神经退行性疾病认识上的一个里程碑式的发现。它已经极大地影响了这些疾病的诊断、调查和感知方式，并提供了两种临床上截然不同的疾病--ALS和FTD之间的机制联系。它还为旨在改善疾病的基因治疗努力提供了一个明确的治疗目标，这种努力已经很好地进行了。 2018年，我们与马萨诸塞大学的约翰·兰德斯合作，发表了一项关于ALS的大型全基因组关联研究。这项工作发现KIF5A基因突变是家族性和散发性疾病的原因之一。 2019年，我们发表了一篇数据驱动的孟德尔随机化论文，其中我们将高胆固醇确定为ALS的风险因素。 在2021年，我们发表了(I)一篇我们将路径分析应用于ALS的论文，(Ii)一篇我们分析全基因组序列数据以确定HTT是ALS/FTD基因的论文，(Iii)一篇我们确定了一种潜在的青少年ALS可治疗形式的论文。 2022年，我们发表了(I)一篇我们在重症肌无力中进行了全基因组关联研究的论文；(Ii)一篇我们使用机器学习来确定ALS人群中的临床亚型的论文；(Iii)一篇我们确定KIF5A基因突变通过有毒的功能获得机制导致运动神经元变性的论文。 该实验室正在进行的项目包括：(1)对更多的家族性肌萎缩侧索硬化症样本进行基因组测序，以寻找运动神经元变性的致病基因。这些案件的DNA是从我们的合作者Adriano Chio(意大利)那里获得的，以及我们在当地和全国招募受试者的努力，这些受试者的重点是收集多样化和包容性的样本。 总而言之，今年在使用基因组分析和先进的生物信息学方法来揭开肌萎缩侧索硬化症方面取得了令人难以置信的成功。这些研究中的每一项都使用了大量的研究对象，并利用了NIA神经遗传学实验室提供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和与年龄相关的活动能力下降中的作用。

Amyotrophic lateral sclerosis (ALS; Lou Gehrig's 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. 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 on 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. Traynor's 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 affected 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 a large 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. In 2021, we published (i) a paper in which we applied pathway analysis to ALS, (ii) a paper in which we analyzed whole-genome sequence data to identify HTT as an ALS/FTD gene; (iii) a paper in which we identified a potentially treatable form of juvenile ALS. In 2022, we published (i) a paper in which we performed a genome-wide association study in myasthenia gravis; (ii) a paper in which we used machine learning to identify the clinical subtypes within the ALS population; (iii) a paper in which we determined that mutations in the KIF5A gene cause motor neuron degeneration through a toxic gain of function mechanism. 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 was obtained from our collaborators, Adriano Chio (Italy), as well as our efforts to recruit subjects locally and nationally that are focused on collecting diverse and inclusive samples. In summary, the current year has been incredibly successful in using genomic analyses and advanced bioinformatic approaches to unravel ALS. 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.