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，可导致快速进行性瘫痪和呼吸衰竭。ALS是西方世界第三大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。 2011年，神经肌肉疾病研究科（NDRS），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，Traynor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%的临床诊断为阿尔茨海默病的患者的基础是相同的大六核苷酸重复扩增。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，并提供了两种临床上不同的疾病，ALS和FTD之间的机制联系。它还为旨在改善疾病的基因治疗工作提供了一个独特的治疗靶点，这种努力已经在进行中。 2018年，我们与马萨诸塞州大学的John Landers合作发表了一项大型ALS全基因组关联研究。这项工作确定了KIF 5A基因突变是家族性和散发性疾病的原因。 2019年，我们发表了一篇数据驱动的孟德尔随机化论文，其中我们将胆固醇升高确定为ALS的风险因素。 于2021年，我们发表了（i）一篇将通路分析应用于ALS的论文;（ii）一篇分析全基因组序列数据以鉴定HTT为ALS/FTD基因的论文;（iii）一篇鉴定出一种可能可治疗的幼年型ALS的论文。 于2022年，我们发表了（i）一篇关于我们对重症肌无力进行全基因组关联研究的论文;（ii）一篇关于我们使用机器学习识别ALS人群中的临床亚型的论文;（iii）一篇关于我们确定KIF 5A基因突变通过毒性功能获得机制导致运动神经元变性的论文。 2023年，我们发表了一篇综述论文，描述了ALS的遗传学以及如何将其扩展到治疗开发。 实验室正在进行的项目包括（1）对其他家族性ALS样本进行基因组测序，以寻找运动神经元变性的致病基因。这些病例的DNA来自我们的合作者Adriano Chio（意大利），以及我们在当地和全国范围内招募受试者的努力，这些受试者专注于收集多样化和包容性的样本。 总之，今年在使用基因组分析和先进的生物信息学方法来解开ALS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，并利用了神经遗传学实验室、NIA和Biowulf的计算资源内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。

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. In 2023, we published a review paper describing the genetics of ALS and how it can be extended to therapeutic development. 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 and the computational resources at Biowulf. 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.