Genetic etiology of Amyotrophic Lateral Sclerosis

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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.