Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Amyotrophic lateral sclerosis: translating genetic discoveries into therapies

Nature Reviews Genetics volume 24, pages 642–658 (2023)Cite this article

Subjects

Abstract

Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene–environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Proportion of familial and sporadic ALS cases attributed to mutations in the corresponding disease-causing genes.
Fig. 2: Thirty years of gene discovery in ALS and FTD.
Fig. 3: Frequency of causal mutations in the four most common ALS genes in diverse populations.
Fig. 4: A model of ALS that integrates genetics, environment and ageing.

Similar content being viewed by others

References

  1. Rowland, L. P. & Shneider, N. A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688–1700 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Kumar, D. R., Aslinia, F., Yale, S. H. & Mazza, J. J. Jean-Martin Charcot: the father of neurology. Clin. Med. Res. 9, 46–49 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chio, A. et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41, 118–130 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Xu, L. et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J. Neurol. 267, 944–953 (2020).

    Article  PubMed  Google Scholar 

  5. U.S. Food and Drug Administration. Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting [online], https://www.youtube.com/watch?v=AVVZMMvDOUg (2022).

  6. Arthur, K. C. et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat. Commun. 7, 12408 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Achtert, K. & Kerkemeyer, L. The economic burden of amyotrophic lateral sclerosis: a systematic review. Eur. J. Health Econ. 22, 1151–1166 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Chio, A., Gauthier, A., Calvo, A., Ghiglione, P. & Mutani, R. Caregiver burden and patients’ perception of being a burden in ALS. Neurology 64, 1780–1782 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Wicks, P. The ALS Ice Bucket Challenge – can a splash of water reinvigorate a field? Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 479–480 (2014).

    Article  PubMed  Google Scholar 

  10. Sohn, E. Fundraising: the Ice Bucket Challenge delivers. Nature 550, S113–S114 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Goutman, S. A. et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 21, 465–479 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Renton, A. E., Chio, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Keller, M. F. et al. Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. JAMA Neurol. 71, 1123–1134 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Al-Chalabi, A. et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J. Neurol. Neurosurg. Psychiatry 81, 1324–1326 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Fang, F. et al. Familial aggregation of amyotrophic lateral sclerosis. Ann. Neurol. 66, 94–99 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chia, R., Chio, A. & Traynor, B. J. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol. 17, 94–102 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Lopez, E. R., Borschel, W. F. & Traynor, B. J. New antisense oligonucleotide therapies reach first base in ALS. Nat. Med. 28, 25–27 (2022).

    Article  CAS  PubMed  Google Scholar 

  18. Siddique, T. et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N. Engl. J. Med. 324, 1381–1384 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993). This is the first study to identify SOD1 mutations as the genetic cause of familial ALS.

    Article  CAS  PubMed  Google Scholar 

  20. Abel, O., Powell, J. F., Andersen, P. M. & Al-Chalabi, A. ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum. Mutat. 33, 1345–1351 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. McCann, E. P. et al. Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis. J. Med. Genet. 58, 87–95 (2021).

    Article  CAS  Google Scholar 

  22. Andersen, P. M. et al. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. Brain 119, 1153–1172 (1996).

    Article  PubMed  Google Scholar 

  23. Parton, M. J. et al. D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. Hum. Mutat. 20, 473 (2002).

    Article  PubMed  Google Scholar 

  24. Feneberg, E., Turner, M. R., Ansorge, O. & Talbot, K. Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology. Neurology 95, 595–596 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Cudkowicz, M. E. et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41, 210–221 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Berdynski, M. et al. Recurrent G41S mutation in Cu/Zn superoxide dismutase gene (SOD1) causing familial amyotrophic lateral sclerosis in a large Polish family. Amyotroph. Lateral Scler. 13, 132–136 (2012).

    Article  PubMed  Google Scholar 

  27. Berdynski, M. et al. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci. Rep. 12, 103 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kuzma-Kozakiewicz, M. et al. Putative founder effect in the Polish, Iranian and United States populations for the L144S SOD1 mutation associated with slowly uniform phenotype of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 22, 80–85 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Bernard, E. et al. Clinical and molecular landscape of ALS patients with SOD1 mutations: novel pathogenic variants and novel phenotypes. A single ALS center study. Int. J. Mol. Sci. 21, 6807 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gamez, J. et al. Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1. J. Neurol. Sci. 247, 21–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Hou, L. et al. Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China. Sci. Rep. 6, 32478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hayashi, Y., Homma, K. & Ichijo, H. SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS. Adv. Biol. Regul. 60, 95–104 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Bosco, D. A. et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat. Neurosci. 13, 1396–1403 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Raoul, C. et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat. Med. 11, 423–428 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Ralph, G. S. et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat. Med. 11, 429–433 (2005). The first study to show the therapeutic efficacy of RNAi in ALS.

    Article  CAS  PubMed  Google Scholar 

  36. Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290–2296 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006). This study was the first to identify cytoplasmic accumulation and nuclear depletion of TDP43 in motor neurons of patients with ALS.

    Article  CAS  PubMed  Google Scholar 

  38. Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008). Kabashi et al. (2008) and Sreedharan et al. (2008) were the first reports of pathogenic TARDBP mutations in ALS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Turner, M. R. et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12, 310–322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Besser, L. M., Teylan, M. A. & Nelson, P. T. Limbic predominant age-related TDP-43 encephalopathy (LATE): clinical and neuropathological associations. J. Neuropathol. Exp. Neurol. 79, 305–313 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Suk, T. R. & Rousseaux, M. W. C. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol. Neurodegener. 15, 45 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nonaka, T. et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124–134 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Nomura, T. et al. Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J. Biol. Chem. 289, 1192–1202 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Chia, R. et al. Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS ONE 5, e10627 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kwiatkowski, T. J. Jr et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009). Kwiatkowski et al. (2009) and Vance et al. (2009) were the first reports of pathogenic FUS mutations in ALS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chio, A. et al. A de novo missense mutation of the FUS gene in a “true” sporadic ALS case. Neurobiol. Aging 32, 553 e523–553 e556 (2011).

    Article  Google Scholar 

  49. Suzuki, N. et al. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. J. Hum. Genet. 55, 252–254 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Lattante, S., Rouleau, G. A. & Kabashi, E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum. Mutat. 34, 812–826 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Hubers, A. et al. De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients. Neurobiol. Aging 36, 3117 e3111–3117 e3116 (2015).

    Article  Google Scholar 

  52. Kim, S. H., Shanware, N. P., Bowler, M. J. & Tibbetts, R. S. Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J. Biol. Chem. 285, 34097–34105 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Khalfallah, Y. et al. TDP-43 regulation of stress granule dynamics in neurodegenerative disease-relevant cell types. Sci. Rep. 8, 7551 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Bosco, D. A. et al. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 19, 4160–4175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). Renton et al. (2011) and DeJesus-Hernandez et al. (2011) were the first studies that identified GGGGCC repeat expansion in C9orf72 in ALS and FTD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012). This study was among the first studies to evaluate the genetics of ALS and FTD globally and across populations of different ancestries.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dols-Icardo, O. et al. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. 23, 749–754 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Ebbert, M. T. W. et al. Long-read sequencing across the C9orf72 ‘GGGGCC’ repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Mol. Neurodegener. 13, 46 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. van der Ende, E. L. et al. Unravelling the clinical spectrum and the role of repeat length in C9ORF72 repeat expansions. J. Neurol. Neurosurg. Psychiatry 92, 502–509 (2021).

    Article  PubMed  Google Scholar 

  61. Gijselinck, I. et al. The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol. Psychiatry 21, 1112–1124 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Nordin, A. et al. Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum. Mol. Genet. 24, 3133–3142 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Beck, J. et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am. J. Hum. Genet. 92, 345–353 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xu, Z. et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl Acad. Sci. USA 110, 7778–7783 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Balendra, R. & Isaacs, A. M. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat. Rev. Neurol. 14, 544–558 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fumagalli, L. et al. C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Sci. Adv. 7, eabg3013 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Shi, Y. et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313–325 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Abramzon, Y. A., Fratta, P., Traynor, B. J. & Chia, R. The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia. Front. Neurosci. 14, 42 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Majounie, E. et al. Repeat expansion in C9ORF72 in Alzheimer’s disease. N. Engl. J. Med. 366, 283–284 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kenna, K. P. et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat. Genet. 48, 1037–1042 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nicolas, A. et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97, 1268–1283 e1266 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brenner, D. et al. Hot-spot KIF5A mutations cause familial ALS. Brain 141, 688–697 (2018). Nicolas et al. (2018) and Brenner et al. (2018) were the first reports of pathogenic KIF5A mutations in ALS.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Saez-Atienzar, S. et al. Identification of a pathogenic intronic KIF5A mutation in an ALS–FTD kindred. Neurology 95, 1015–1018 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Baron, D. M. et al. ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. Cell Rep. 39, 110598 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Castellanos-Montiel, M. J., Chaineau, M. & Durcan, T. M. The neglected genes of ALS: cytoskeletal dynamics impact synaptic degeneration in ALS. Front. Cell Neurosci. 14, 594975 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wenting, G., Laura, F. & Ludo Van Den, B. in Amyotrophic Lateral Sclerosis (ed. Hegde, L. M.) (IntechOpen, 2020).

  78. Tunca, C. et al. ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree. Eur. J. Hum. Genet. 26, 745–748 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhu, Z. Y. et al. A novel homozygous mutation in ERLIN1 gene causing spastic paraplegia 62 and literature review. Eur. J. Med. Genet. 65, 104608 (2022).

    Article  CAS  PubMed  Google Scholar 

  80. Novarino, G. et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343, 506–511 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Egorova, P. A. & Bezprozvanny, I. B. Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J. 285, 3547–3565 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Higo, T. et al. Mechanism of ER stress-induced brain damage by IP3 receptor. Neuron 68, 865–878 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Casey, J. P. et al. A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns. J. Neurol. 264, 1444–1453 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Farhan, S. M. K. et al. Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein. Nat. Neurosci. 22, 1966–1974 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jih, K. Y., Tsai, P. C., Tsai, Y. S., Liao, Y. C. & Lee, Y. C. Rapid progressive ALS in a patient with a DNAJC7 loss-of-function mutation. Neurol. Genet. 6, e503 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. He, J. et al. Validation of the pathogenic role of rare DNAJC7 variants in Chinese patients with amyotrophic lateral sclerosis. Neurobiol. Aging 106, 314 e311–314 e316 (2021).

    Article  Google Scholar 

  87. Wang, M. et al. A novel potentially pathogenic rare variant in the DNAJC7 gene identified in amyotrophic lateral sclerosis patients from mainland China. Front. Genet. 11, 821 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Tohnai, G. et al. Mutation screening of the DNAJC7 gene in Japanese patients with sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 113, 131–136 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Dilliott, A. A. et al. DnaJC7 in amyotrophic lateral sclerosis. Int. J. Mol. Sci. 23, 4076 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jinwal, U. K. et al. Cdc37/Hsp90 protein complex disruption triggers an autophagic clearance cascade for TDP-43 protein. J. Biol. Chem. 287, 24814–24820 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dewan, R. et al. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 109, 448–460 e444 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Hickman, R. A. et al. Amyotrophic lateral sclerosis is over-represented in two Huntington’s disease brain bank cohorts: further evidence to support genetic pleiotropy of pathogenic HTT gene expansion. Acta Neuropathol. 143, 105–108 (2022).

    Article  CAS  PubMed  Google Scholar 

  93. Dewan, R. et al. CAG somatic instability in a Huntington disease expansion carrier presenting with a progressive supranuclear palsy-like phenotype. Mov. Disord. 37, 1555–1557 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Grima, J. C. et al. Mutant huntingtin disrupts the nuclear pore complex. Neuron 94, 93–107 e106 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129–133 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tabrizi, S. J. et al. Targeting huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Johnson, J. O. et al. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. JAMA Neurol. 78, 1236–1248 (2021).

    Article  PubMed  Google Scholar 

  98. Mohassel, P. et al. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis. Nat. Med. 27, 1197–1204 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bejaoui, K. et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat. Genet. 27, 261–262 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Penno, A. et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J. Biol. Chem. 285, 11178–11187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Garofalo, K. et al. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J. Clin. Invest. 121, 4735–4745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Buniello, A. et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–D1012 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Schymick, J. C. et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 6, 322–328 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. van Es, M. A. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat. Genet. 41, 1083–1087 (2009).

    Article  PubMed  Google Scholar 

  105. Laaksovirta, H. et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9, 978–985 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shatunov, A. et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 9, 986–994 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043–1048 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Benyamin, B. et al. Cross-ethnic meta-analysis identifies association of the GPX3–TNIP1 locus with amyotrophic lateral sclerosis. Nat. Commun. 8, 611 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. van Rheenen, W. et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat. Genet. 53, 1636–1648 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Fogh, I. et al. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum. Mol. Genet. 23, 2220–2231 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Nakamura, R. et al. A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. Commun. Biol. 3, 526 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Brenner, D. et al. NEK1 mutations in familial amyotrophic lateral sclerosis. Brain 139, e28 (2016).

    Article  PubMed  Google Scholar 

  115. Saez-Atienzar, S. et al. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci. Adv. 7, eabd9036 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ho, W. Y. et al. The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy 15, 827–842 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yang, M. et al. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci. Adv. 2, e1601167 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Maekawa, S. et al. Cortical selective vulnerability in motor neuron disease: a morphometric study. Brain 127, 1237–1251 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Maniatis, S. et al. Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364, 89–93 (2019).

    Article  CAS  PubMed  Google Scholar 

  120. Humphrey, J. et al. Integrative transcriptomic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes. Nat. Neurosci. 26, 150–162 (2023).

    Article  CAS  PubMed  Google Scholar 

  121. Lee, H. et al. Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS. Nat. Neurosci. 24, 1673–1685 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tazelaar, G. H. P. et al. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Commun. 2, fcaa064 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Daoud, H. et al. Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch. Neurol. 68, 739–742 (2011).

    Article  PubMed  Google Scholar 

  125. Glass, J. D. et al. ATXN2 intermediate expansions in amyotrophic lateral sclerosis. Brain 145, 2671–2676 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Blauw, H. M. et al. NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2497–2502 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Al Khleifat, A. et al. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ Genom. Med. 7, 8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ross, J. P., Dion, P. A. & Rouleau, G. A. in Spectrums of Amyotrophic Lateral Sclerosis (eds Shaw, C. A. & Morrice, J. R.) 17–34 (Wiley, 2021).

  129. Valdmanis, P. N. et al. A mutation that creates a pseudoexon in SOD1 causes familial ALS. Ann. Hum. Genet. 73, 652–657 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Morgan, S. et al. A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. Brain 140, 1611–1618 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Eitan, C. et al. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3’UTR protect against ALS. Nat. Neurosci. 25, 433–445 (2022).

    Article  CAS  PubMed  Google Scholar 

  132. Birve, A. et al. A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis. Hum. Mol. Genet. 19, 4201–4206 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Kawata, A. et al. Aberrant splicing of human Cu/Zn superoxide dismutase (SOD1) RNA transcripts. Neuroreport 11, 2649–2653 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Jeong, Y. H. et al. Tdp-43 cryptic exons are highly variable between cell types. Mol. Neurodegener. 12, 13 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650–655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Brown, A. L. et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature 603, 131–137 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Alexander, M. D. et al. “True” sporadic ALS associated with a novel SOD-1 mutation. Ann. Neurol. 52, 680–683 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Muller, K. et al. De novo mutations in SOD1 are a cause of ALS. J. Neurol. Neurosurg. Psychiatry 93, 201–206 (2022).

    Article  PubMed  Google Scholar 

  139. Garcia-Montojo, M., Doucet-O’Hare, T., Henderson, L. & Nath, A. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit. Rev. Microbiol. 44, 715–738 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. MacGowan, D. J. et al. A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS. Neurology 68, 1944–1946 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 7, 307ra153 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Garcia-Montojo, M. et al. Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy. J. Neurol. Sci. 423, 117358 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chio, A. et al. Cognitive impairment across ALS clinical stages in a population-based cohort. Neurology 93, e984–e994 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Dupuis, L. et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 70, 1004–1009 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Abdel-Khalik, J. et al. Defective cholesterol metabolism in amyotrophic lateral sclerosis. J. Lipid Res. 58, 267–278 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Dodge, J. C. et al. Neutral lipid cacostasis contributes to disease pathogenesis in amyotrophic lateral sclerosis. J. Neurosci. 40, 9137–9147 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Andres-Benito, P. et al. Lipid alterations in human frontal cortex in ALS-FTLD-TDP43 proteinopathy spectrum are partly related to peroxisome impairment. Neuropathol. Appl. Neurobiol. 47, 544–563 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ikeda, K., Hirayama, T., Takazawa, T., Kawabe, K. & Iwasaki, Y. Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study. Intern. Med. 51, 1501–1508 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. Thompson, A. G., Talbot, K. & Turner, M. R. Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 93, 75–81 (2022).

    Article  PubMed  Google Scholar 

  152. Cutler, R. G., Pedersen, W. A., Camandola, S., Rothstein, J. D. & Mattson, M. P. Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann. Neurol. 52, 448–457 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Theofilopoulos, S. et al. Cholestenoic acids regulate motor neuron survival via liver X receptors. J. Clin. Invest. 124, 4829–4842 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Dodge, J. C. et al. Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 112, 8100–8105 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. D’Amico, E. et al. Metabolic abnormalities, dietary risk factors and nutritional management in amyotrophic lateral sclerosis. Nutrients 13, 2273 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Chio, A. et al. Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology 73, 1681–1685 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Yang, J. W. et al. Hypolipidemia in patients with amyotrophic lateral sclerosis: a possible gender difference? J. Clin. Neurol. 9, 125–129 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Sutedja, N. A. et al. Beneficial vascular risk profile is associated with amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 82, 638–642 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Hartmann, H., Ho, W. Y., Chang, J. C. & Ling, S. C. Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon? FEBS J. 289, 7688–7709 (2022).

    Article  CAS  PubMed  Google Scholar 

  160. Vasta, R., Chia, R., Traynor, B. J. & Chio, A. Unraveling the complex interplay between genes, environment, and climate in ALS. EBioMedicine 75, 103795 (2022).

    Article  PubMed  Google Scholar 

  161. Bandres-Ciga, S. et al. Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Ann. Neurol. 85, 470–481 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Goutman, S. A. et al. Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts. Brain 145, 4425–4439 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Zeng, P., Wang, T., Zheng, J. & Zhou, X. Causal association of type 2 diabetes with amyotrophic lateral sclerosis: new evidence from Mendelian randomization using GWAS summary statistics. BMC Med. 17, 225 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Zhang, L., Tang, L., Huang, T. & Fan, D. Association between type 2 diabetes and amyotrophic lateral sclerosis. Sci. Rep. 12, 2544 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen, H. et al. Type 2 diabetes mellitus and amyotrophic lateral sclerosis: genetic overlap, causality, and mediation. J. Clin. Endocrinol. Metab. 106, e4497–e4508 (2021).

    Article  PubMed  Google Scholar 

  166. Julian, T. H. et al. A review of Mendelian randomization in amyotrophic lateral sclerosis. Brain 145, 832–842 (2022).

    Article  PubMed  Google Scholar 

  167. D’Ovidio, F. et al. The role of pre-morbid diabetes on developing amyotrophic lateral sclerosis. Eur. J. Neurol. 25, 164–170 (2018).

    Article  PubMed  Google Scholar 

  168. Nakken, O., Meyer, H. E., Stigum, H. & Holmoy, T. High BMI is associated with low ALS risk: a population-based study. Neurology 93, e424–e432 (2019).

    Article  PubMed  Google Scholar 

  169. Vasta, R., D’Ovidio, F., Logroscino, G. & Chio, A. The links between diabetes mellitus and amyotrophic lateral sclerosis. Neurol. Sci. 42, 1377–1387 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Reid, E. et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, 1189–1194 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Crimella, C. et al. Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot–Marie-Tooth type 2. Clin. Genet. 82, 157–164 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Cronin, S., Hardiman, O. & Traynor, B. J. Ethnic variation in the incidence of ALS: a systematic review. Neurology 68, 1002–1007 (2007).

    Article  PubMed  Google Scholar 

  173. Zou, Z. Y. et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 88, 540–549 (2017).

    Article  PubMed  Google Scholar 

  174. Pliner, H. A., Mann, D. M. & Traynor, B. J. Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion. Acta Neuropathol. 127, 391–396 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Suzuki, N., Nishiyama, A., Warita, H. & Aoki, M. Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy. J. Hum. Genet. 68, 131–152 (2023).

    Article  CAS  PubMed  Google Scholar 

  176. Dombroski, B. A. et al. C9orf72 hexanucleotide repeat expansion and Guam amyotrophic lateral sclerosis-Parkinsonism-dementia complex. JAMA Neurol. 70, 742–745 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Logroscino, G. & Piccininni, M. Amyotrophic lateral sclerosis descriptive epidemiology: the origin of geographic difference. Neuroepidemiology 52, 93–103 (2019).

    Article  PubMed  Google Scholar 

  178. Chio, A. et al. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch. Neurol. 68, 594–598 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Chadi, G. et al. Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 249–255 (2017).

    Article  CAS  PubMed  Google Scholar 

  180. Johnson, J. O. et al. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 135, 2875–2882 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Green, P. et al. Brown–Vialetto–Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am. J. Hum. Genet. 86, 485–489 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Bandres-Ciga, S., Noyce, A. J. & Traynor, B. J. Mendelian randomization — a journey from obscurity to center stage with a few potholes along the way. JAMA Neurol. 77, 7–8 (2020).

    Article  PubMed  Google Scholar 

  183. Pingault, J. B. et al. Using genetic data to strengthen causal inference in observational research. Nat. Rev. Genet. 19, 566–580 (2018).

    Article  CAS  PubMed  Google Scholar 

  184. Ebbert, M. T. W., Lank, R. J. & Belzil, V. V. An epigenetic spin ALS FTD. Adv. Neurobiol. 20, 1–29 (2018).

    Article  PubMed  Google Scholar 

  185. Bennett, S. A., Tanaz, R., Cobos, S. N. & Torrente, M. P. Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease. Transl. Res. 204, 19–30 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Dolinar, A., Ravnik-Glavac, M. & Glavac, D. Epigenetic mechanisms in amyotrophic lateral sclerosis: a short review. Mech. Ageing Dev. 174, 103–110 (2018).

    Article  CAS  PubMed  Google Scholar 

  187. Hop, P. J. et al. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Sci. Transl. Med. 14, eabj0264 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. McMillan, C. T. et al. C9orf72 promoter hypermethylation is neuroprotective: neuroimaging and neuropathologic evidence. Neurology 84, 1622–1630 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Rothman, K. J. Causes. Am. J. Epidemiol. 104, 587–592 (1976).

    Article  CAS  PubMed  Google Scholar 

  191. Alfahad, T. & Nath, A. Retroviruses and amyotrophic lateral sclerosis. Antivir. Res. 99, 180–187 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Van Damme, P., Robberecht, W. & Van Den Bosch, L. Modelling amyotrophic lateral sclerosis: progress and possibilities. Dis. Model. Mech. 10, 537–549 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Al-Chalabi, A. et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol. 13, 1108–1113 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Traynor, B. J. & Singleton, A. B. Nature versus nurture: death of a dogma, and the road ahead. Neuron 68, 196–200 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Boyle, E. A., Li, Y. I. & Pritchard, J. K. An expanded view of complex traits: from polygenic to omnigenic. Cell 169, 1177–1186 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Bensimon, G., Lacomblez, L. & Meininger, V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 330, 585–591 (1994).

    Article  CAS  PubMed  Google Scholar 

  197. Writing, G. & Edaravone, A. L. S. S. G. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 16, 505–512 (2017).

    Article  Google Scholar 

  198. Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Sufit, R. L., Ajroud-Driss, S., Casey, P. & Kessler, J. A. Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 269–278 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Korobeynikov, V. A., Lyashchenko, A. K., Blanco-Redondo, B., Jafar-Nejad, P. & Shneider, N. A. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat. Med. 28, 104–116 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Mullard, A. ALS antisense drug falters in phase III. Nat. Rev. Drug Discov. 20, 883–885 (2021).

    Article  CAS  PubMed  Google Scholar 

  202. Biogen Investor Relations. New 12-Month Tofersen Data Presented at ENCALS Meeting Show Clinically Meaningful Benefit in People With SOD1-ALS [Online], https://investors.biogen.com/news-releases/news-release-details/new-12-month-tofersen-data-presented-encals-meeting-show (2022).

  203. Tabrizi, S. J. et al. Potential disease-modifying therapies for Huntington’s disease: lessons learned and future opportunities. Lancet Neurol. 21, 645–658 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Benatar, M. et al. Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the ATLAS study. Neurotherapeutics 19, 1248–1258 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Tran, H. et al. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nat. Med. 28, 117–124 (2022).

    Article  CAS  PubMed  Google Scholar 

  206. Becker, L. A. et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Sullivan, J. M. et al. Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system. J. Transl. Med. 18, 309 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Belov, V. et al. Large-volume intrathecal administrations: impact on CSF pressure and safety implications. Front. Neurosci. 15, 604197 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Nagata, T. et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS. Nat. Biotechnol. 39, 1529–1536 (2021).

    Article  CAS  PubMed  Google Scholar 

  211. Gennemark, P. et al. An oral antisense oligonucleotide for PCSK9 inhibition. Sci. Transl. Med. 13, eabe9117 (2021).

    Article  CAS  PubMed  Google Scholar 

  212. Figlewicz, D. A. et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum. Mol. Genet. 3, 1757–1761 (1994).

    Article  CAS  PubMed  Google Scholar 

  213. Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat. Genet. 29, 160–165 (2001).

    Article  CAS  PubMed  Google Scholar 

  214. Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  215. Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).

    Article  CAS  PubMed  Google Scholar 

  218. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Orlacchio, A. et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133, 591–598 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).

    Article  CAS  PubMed  Google Scholar 

  221. Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

    Article  PubMed  Google Scholar 

  223. Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324–331 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137, 2329–2345 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Williams, K. L. et al. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat. Commun. 7, 11253 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Smith, B. N. et al. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci. Transl. Med. 9, eaad9157 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Cooper-Knock, J. et al. Mutations in the glycosyltransferase domain of GLT8D1 are associated with familial amyotrophic lateral sclerosis. Cell Rep. 26, 2298–2306 e2295 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Grassano, M. et al. Systematic evaluation of genetic mutations in ALS: a population-based study. J. Neurol. Neurosurg. Psychiatry 93, 1190–1193 (2022).

    Article  PubMed  Google Scholar 

  232. McCann, E. P. et al. The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia. Clin. Genet. 92, 259–266 (2017).

    Article  CAS  PubMed  Google Scholar 

  233. Smith, B. N. et al. The C9ORF72 expansion mutation is a common cause of ALS+/− FTD in Europe and has a single founder. Eur. J. Hum. Genet. 21, 102–108 (2013).

    Article  CAS  PubMed  Google Scholar 

  234. Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Shahryari, A. et al. Development and clinical translation of approved gene therapy products for genetic disorders. Front. Genet. 10, 868 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Kwok, A., Raulf, N. & Habib, N. Developing small activating RNA as a therapeutic: current challenges and promises. Ther. Deliv. 10, 151–164 (2019).

    Article  CAS  PubMed  Google Scholar 

  237. Wengert, E. R. et al. Targeted augmentation of nuclear gene output (TANGO) of Scn1a rescues parvalbumin interneuron excitability and reduces seizures in a mouse model of Dravet Syndrome. Brain Res. 1775, 147743 (2022).

    Article  CAS  PubMed  Google Scholar 

  238. Sanders, R. FDA approves first test of CRISPR to correct genetic defect causing sickle cell disease [online], https://news.berkeley.edu/2021/03/30/fda-approves-first-test-of-crispr-to-correct-genetic-defect-causing-sickle-cell-disease/ (2021).

  239. Frangoul, H. et al. CRISPR–Cas9 gene editing for sickle cell disease and beta-thalassemia. N. Engl. J. Med. 384, 252–260 (2021).

    Article  CAS  PubMed  Google Scholar 

  240. No authors listed. FDA approves hereditary blindness gene therapy. Nat. Biotechnol. 36, 6 (2018).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIH Intramural Research Program, the US National Institute on Aging (NIA) grant Z01-AG000949-02, the US National Institute of Neurological Disorders and Stroke (NINDS) grant NS03130 and the US National Center for Advancing Translational Sciences (NCATS).

Author information

Authors and Affiliations

  1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    Fulya Akçimen, Ruth Chia & Bryan J. Traynor

  2. Therapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA

    Elia R. Lopez & Bryan J. Traynor

  3. Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA

    John E. Landers

  4. Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Avindra Nath

  5. Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy

    Adriano Chiò

  6. Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy

    Adriano Chiò

  7. Azienda Ospedaliero Universitaria Citta‘ della Salute e della Scienza, Turin, Italy

    Adriano Chiò

  8. Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA

    Bryan J. Traynor

Authors
  1. Fulya Akçimen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elia R. Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John E. Landers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Avindra Nath
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adriano Chiò
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruth Chia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bryan J. Traynor
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors wrote the manuscript, researched content for the article, substantially contributed to discussion of content, and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Fulya Akçimen or Bryan J. Traynor.

Ethics declarations

Competing interests

B.J.T. holds a patent on the diagnostic and therapeutic applications of the pathogenic repeat expansion in C9orf72. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Genetics thanks Karen Morrison, who co-reviewed with Gavin McCluskey, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Answer ALS: https://www.answerals.org/

Clinical trial information for Engensis (VM202): https://alsnewstoday.com/vm202/

dbGaP: https://www.ncbi.nlm.nih.gov/gap/

N=1 Collaborative network: https://www.n1collaborative.org/

New York Genome Center ALS Consortium: https://www.nygenome.org/als-consortium/

Online Mendelian Inheritance in Man: https://www.omim.org/

Project MinE: https://www.projectmine.com/

Safety study of VM202 to treat amyotrophic lateral sclerosis: https://clinicaltrials.gov/ct2/show/NCT02039401

Glossary

De novo mutations

Mutations not inherited from either parent and present for the first time in a family.

End point

The targeted outcome of a clinical trial to determine the efficacy and safety of the therapy. The amyotrophic lateral sclerosis functional rating — revised (ALSFRS-R) score is the commonly used primary end point for ALS clinical trials.

Enrichment analysis

A statistical approach to identify over-represented or differentially expressed genes or biological pathways contributing to a phenotype.

Familial aggregation studies

Methods to assess the relative risk of a trait in affected family members compared with unaffected family members. Familial aggregation is the tendency for a trait to occur or cluster in multiple family members beyond what would be expected by chance.

Founder effect

The reduction in genetic diversity when a newly established population is descendent from a small number of ancestors.

Genome-wide association studies

(GWAS). Studies in which genetic variants across the genome are genotyped and tested for association with a trait.

Haploinsufficiency

A situation in which a diploid organism has only one copy of a gene when both copies are required for proper function.

Hydrocephalus

Abnormal cerebrospinal fluid in the ventricles of the brain.

Linkage analysis

An approach that examines the co-segregation of the chromosomal region (or regions) with traits of interest, usually designed to localize disease-causing genes in co-segregating segments.

Mendelian randomization

The use of genetic variation to address the causal effect of one trait on another, minimizing the issues of confounding and reverse causality.

Mimic syndromes

A diverse group of conditions, the clinical features of which may resemble amyotrophic lateral sclerosis.

Missing heritability

The discrepancy between the heritability explained by trait-associated genetic variants from genome-wide association studies and the amount of total heritability from familial aggregation or twin studies.

Prion-like motifs

Unstructured protein domains that can undergo conformational switches in response to environmental stress. Their phase transition activity renders RNA-binding proteins prone to misfolding in neurodegenerative diseases.

Segregation analysis

A study that examines the carrier status of a genetic variant in the affected and unaffected members of a family. It is used to validate whether a specific genetic variant is causal for the disease in a family and the established mode of inheritance based on the pedigree structure.

Twin studies

Studies that compare the resemblance of monozygotic (identical) and dizygotic (non-identical) twins. An increased concordance rate in monozygotic twins compared with dizygotic twins provides evidence of a genetic component.

Whole-exome sequencing

Targeted sequencing method that selectively determines exome sequences, which are highly enriched for protein-coding regions.

Whole-genome sequencing

Sequencing method that examines the entire genome of an individual.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akçimen, F., Lopez, E.R., Landers, J.E. et al. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies. Nat Rev Genet 24, 642–658 (2023). https://doi.org/10.1038/s41576-023-00592-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-023-00592-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research