Genetic aspects of amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis is a progressive, incurable neurodegenerative disease characterized by motor neuron loss and the development of paralysis and skeletal muscle atrophy. This review focuses on the genetic aspects of amyotrophic lateral sclerosis, with an emphasis on four key genes—C9orf72, SOD1, TARDBP, and FUS—mutations in which account for most familial cases and represent important targets for therapeutic development. The genetic architecture of amyotrophic lateral sclerosis is complex and predominantly determined by monogenic inheritance of mutations. To date, more than 40 amyotrophic lateral sclerosis-associated genes have been identified, differing in prevalence, inheritance patterns, and penetrance. Mutations in C9orf72, SOD1, TARDBP, and FUS lead to disruption of critically important cellular processes. These processes include protein homeostasis, RNA metabolism, mitochondrial function, autophagy, cytoskeletal integrity, and DNA repair. Despite considerable progress, genetic predisposition explains only a portion of amyotrophic lateral sclerosis cases, underscoring the need for further investigation of environmental factors, epigenetic modifications, and accompanying pathophysiologic processes such as oxidative stress and inflammation. Comprehensive studies of molecular-genetic and pathophysiologic mechanisms is essential for the development of effective strategies for early diagnosis and treatment of amyotrophic lateral sclerosis.

About the authors

Kerim K. Nagiev

Kazan State Medical University

Author for correspondence.
Email: drkerim@mail.ru
ORCID iD: 0009-0000-1577-9780
SPIN-code: 1012-0178
Russian Federation, Kazan

Albina Y. Sysoeva

Kazan State Medical University

Email: Sysoeva.albina2015@yandex.ru
ORCID iD: 0009-0003-3852-669X
SPIN-code: 2868-2587
Russian Federation, Kazan

Elza M. Karimullina

Kazan State Medical University

Email: karimullina.elza@mail.ru
ORCID iD: 0009-0002-6365-1444
Russian Federation, Kazan

Liaisan A. Akhmadieva

Kazan State Medical University

Email: lyaisan.akhmadieva@kazangmu.ru
ORCID iD: 0009-0000-4926-3192
SPIN-code: 1497-7867
Russian Federation, Kazan

Ilnur I. Salafutdinov

Kazan (Volga Region) Federal University

Email: IISalafutdinov@kpfu.ru
ORCID iD: 0000-0001-6988-0673
SPIN-code: 4157-2610

Dr. Sci. (Biology)

Russian Federation, Kazan

Marat A. Mukhamedyarov

Kazan State Medical University

Email: marat.muhamedyarov@kazangmu.ru
ORCID iD: 0000-0002-0397-9002
SPIN-code: 6625-7526

MD, Cand. Sci. (Medicine), Professor

Russian Federation, Kazan

References

  1. Barberio J, Lally C, Kupelian V, et al. Estimated familial amyotrophic lateral sclerosis proportion: a literature review and meta-analysis. Neurol Genet. 2023;9(6):e200109. doi: 10.1212/NXG.0000000000200109
  2. Mitsi E, Votsi C, Koutsou P, et al. Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study. Sci Rep. 2024;14(1):30781. doi: 10.1038/s41598-024-80851-y
  3. Costa J, de Carvalho M. Emerging molecular biomarker targets for amyotrophic lateral sclerosis. Clin Chim Acta. 2016;455:7–14. doi: 10.1016/j.cca.2016.01.011
  4. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171. doi: 10.4103/2152-7806.169561
  5. Carrera-Juliá S, Moreno ML, Barrios C, et al. Antioxidant alternatives in the treatment of amyotrophic lateral sclerosis: a comprehensive review. Front Physiol. 2020;11:63. doi: 10.3389/fphys.2020.00063
  6. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118–1130. doi: 10.1159/000351153
  7. Forsgren L, Almay BG, Holmgren G, Wall S. Epidemiology of motor neuron disease in northern Sweden. Acta Neurol Scand. 1983;68(1):20–29. doi: 10.1111/j.1600-0404.1983.tb04810.x
  8. Mukhamedyarov MA, Petrov AM, Grigoryev PN, et al. Amyotrophic lateral sclerosis: modern viewson the pathogenesis and experimental models. Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I.P. Pavlova. 2018;68(5):551–566. doi: 10.1134/S0044467718050106 EDN: YMOUOD
  9. Khabibrakhmanov AN, Akhmadieva LA, Nagiev KK, Mukhamedyarov MA. Mechanisms of neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Annals of Clinical and Experimental Neurology. 2025;19(1):53–61. doi: 10.17816/ACEN.1070 EDN: OCCOHQ
  10. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. doi: 10.1038/nrdp.2017.71
  11. Mukhamedyarov MA, Khabibrakhmanov AN, Zefirov AL. Early dysfunctions in amyotrophic lateral sclerosis: pathogenetic mechanisms and the role in disease initiation. Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology. 2020;14(4):261–266. doi: 10.1134/S1990747820030113 EDN: KCFNVZ
  12. Mukhamedyarov MA, Khabibrakhmanov AN, Khuzakhmetova VF. Early alterations in structural and functional properties in the neuromuscular junctions of mutant FUS mice. Int J Mol Sci. 2023;24(10):9022. doi: 10.3390/ijms24109022 EDN: CCYRHQ
  13. Khairullin AE, Mukhamedyarov MA, Grishin SN, et al. Synaptic aspects of the pathogenesis of autism, amyotrophic lateral sclerosis, and Alzheimer’s disease. Biofizika. 2023;68(1):169–178. doi: 10.31857/S0006302923010192 EDN: OBJWAH
  14. Skvortsova VI, Limborskaya SA, Slominsky PA, et al. Тhe peculiarities of sporadic motor neuron disease associated with D90a and G12R mutations in Russian population. S.S. Korsakov Journal of Neurology and Psychiatry. 2003;103(11):46–52. EDN: MYWFND
  15. Malik R, Wiedau M. Therapeutic approaches targeting protein aggregation in amyotrophic lateral sclerosis. Front Mol Neurosci. 2020;13:98. doi: 10.3389/fnmol.2020.00098
  16. Gu D, Ou S, Tang M, et al. Trauma and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(3-4):170–185. doi: 10.1080/21678421.2020.1861024
  17. Jalilian H, Najafi K, Khosravi Y, Röösli M. Amyotrophic lateral sclerosis, occupational exposure to extremely low frequency magnetic fields and electric shocks: a systematic review and meta-analysis. Rev Environ Health. 2020;36(1):129–142. doi: 10.1515/reveh-2020-0041
  18. Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019t;32(5):771–776. doi: 10.1097/WCO.0000000000000730
  19. Yu Y, Su FC, Callaghan BC, et al. Environmental risk factors and amyotrophic lateral sclerosis (ALS): a case-control study of ALS in Michigan. PLoS One. 2014;9(6):e101186. doi: 10.1371/journal.pone.0101186
  20. Cady J, Allred P, Bali T, et al. Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol. 2015;77(1):100–113. doi: 10.1002/ana.24306
  21. Wang H, Guan L, Deng M. Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy. Front Neurosci. 2023;17:1170996. doi: 10.3389/fnins.2023.1170996
  22. Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400(10360):1363–1380. doi: 10.1016/S0140-6736(22)01272-7
  23. Shpilyukova YuA, Rosliakova AA, Zakharova MN, Illarioshkin SN. Presymptomatic genetic counseling in amyotrophic lateral sclerosis. Neuromuscular Diseases. 2017;7(4):50–55. doi: 10.17650/2222?8721?2017?7?4-50-55 EDN: YLWRCB
  24. Abramycheva NYu, Lysogorskaya EV, Shpilyukova YuA, et al. Molecular structure of amyotrophic lateral sclerosis in Russian population. Neuromuscular Diseases. 2016;6(4):21–27. doi: 10.17650/2222-8721-2016-6-4-21-27 EDN: XIHGBJ
  25. Lysogorskaia EV, Abramycheva NYu, Zakharova MN, et al. Genetic studies of Russian patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2016;17(1-2):135–141. doi: 10.3109/21678421.2015.1107100 EDN: WRIPLB
  26. Abramycheva NY, Lysogorskaia EV, Stepanova MS, et al. C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. Neurobiology of Aging. 2015;36(10):2908.e5–2908.e9. doi: 10.1016/j.neurobiolaging.2015.07.004 EDN: WYMRTF
  27. Levitsky GN, Zakharova EYu, Milovanova NV, et al. Genetic markers of amyotrophic lateral sclerosis in the Russian population. Pharmateca. 2022;(3):16–24. doi: 10.18565/pharmateca.2022.3.16-24
  28. Chia R, Chiò A, Traynor BJ. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol. 2018;17(1):94–102. doi: 10.1016/S1474-4422(17)30401-5
  29. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;364(6435):362. doi: 10.1038/364362c0.
  30. Trist BG, Hilton JB, Hare DJ, et al. Superoxide dismutase 1 in health and disease: how a frontline antioxidant becomes neurotoxic. Angew Chem Int Ed Engl. 2021;60(17):9215–9246. doi: 10.1002/anie.202000451
  31. McAlary L, Aquilina JA, Yerbury JJ. Susceptibility of mutant SOD1 to form a destabilized monomer predicts cellular aggregation and toxicity but not in vitro aggregation propensity. Front Neurosci. 2016;10:499. doi: 10.3389/fnins.2016.00499
  32. Trist BG, Genoud S, Roudeau S, et al. Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord. Brain. 2022;145(9):3108–3130. doi: 10.1093/brain/awac165
  33. Berdyński M, Miszta P, Safranow K, et al. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci Rep. 2022;12(1):103. doi: 10.1038/s41598-021-03891-8
  34. Jo M, Lee S, Jeon YM, et al. The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med. 2020;52(10):1652–1662. doi: 10.1038/s12276-020-00513-7
  35. Lim SM, Nahm M, Kim SH. Proteostasis and ribostasis impairment as common cell death mechanisms in neurodegenerative diseases. J Clin Neurol. 2023;19(2):101–114. doi: 10.3988/jcn.2022.0379
  36. Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–611. doi: 10.1016/j.bbrc.2006.10.093
  37. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–1672. doi: 10.1126/science.1154584.
  38. Berning BA, Walker AK. The pathobiology of TDP-43 C-terminal fragments in ALS and FTLD. Front Neurosci. 2019;13:335. doi: 10.3389/fnins.2019.00335
  39. Yamashita R, Beck G, Yonenobu Y, et al. TDP-43 Proteinopathy presenting with typical symptoms of Parkinson's disease. Mov Disord. 2022;37(7):1561–1563. doi: 10.1002/mds.29048
  40. Meneses A, Koga S, O'Leary J, et al. TDP-43 pathology in Alzheimer's disease. Mol Neurodegener. 2021;16(1):84. doi: 10.1186/s13024-021-00503-x
  41. Estades Ayuso V, Pickles S, Todd T, et al. TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains. Mol Neurodegener. 2023;18(1):57. doi: 10.1186/s13024-023-00646-z
  42. Bai D, Deng F, Jia Q, et al. Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice. Aging Cell. 2024;23(12):e14325. doi: 10.1111/acel.14325
  43. Gao J, Wang L, Huntley ML, et al. Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem. 2018:10.1111/jnc.14327. doi: 10.1111/jnc.14327
  44. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–133. doi: 10.1126/science
  45. Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416–438. doi: 10.1016/j.neuron.2013.07.033
  46. de Boer EMJ, Orie VK, Williams T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2020;92(1):86–95. doi: 10.1136/jnnp-2020-322983
  47. Pesiridis GS, Lee VM, Trojanowski JQ. Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Genet. 2009;18(R2):R156–62. doi: 10.1093/hmg/ddp303
  48. Szewczyk B, Günther R, Japtok J, et al. FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration. Cell Rep. 2023;42(2):112025. doi: 10.1016/j.celrep.2023.112025
  49. Tejido C, Pakravan D, Bosch LVD. Potential therapeutic role of HDAC inhibitors in FUS-ALS. Front Mol Neurosci. 2021;14:686995. doi: 10.3389/fnmol.2021.686995
  50. Deng H, Gao K, Jankovic J. The role of FUS gene variants in neurodegenerative diseases. Nat Rev Neurol. 2014;10(6):337–348. doi: 10.1038/nrneurol.2014.78
  51. Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540–549. doi: 10.1136/jnnp-2016-315018
  52. López-Erauskin J, Tadokoro T, Baughn MW, et al. ALS/FTD-linked mutation in FUS Suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron. 2020;106(2):354. doi: 10.1016/j.neuron.2020.04.006
  53. Sharma A, Lyashchenko AK, Lu L, et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun. 2016;7:10465. doi: 10.1038/ncomms10465
  54. Lagier-Tourenne C, Polymenidou M, Hutt KR, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15(11):1488–97. doi: 10.1038/nn.3230
  55. Zhou Y, Liu S, Liu G, Oztürk A, Hicks GG. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013;9(10):e1003895. doi: 10.1371/journal.pgen.1003895
  56. Merner ND, Girard SL, Catoire H, et al. Exome sequencing identifies FUS mutations as a cause of essential tremor. Am J Hum Genet. 2012;91(2):313–319. doi: 10.1016/j.ajhg.2012.07.002
  57. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–256. doi: 10.1016/j.neuron.2011.09.011
  58. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–268. doi: 10.1016/j.neuron.2011.09.010
  59. Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14(9):544–558. doi: 10.1038/s41582-018-0047-2
  60. Sellier C, Campanari ML, Julie Corbier C, et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016;35(12):1276–1297. doi: 10.15252/embj.201593350
  61. Yang M, Liang C, Swaminathan K, et al. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016;2(9):e1601167. doi: 10.1126/sciadv.1601167
  62. Cleary JD, Ranum LP. New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev. 2017;44:125–134. doi: 10.1016/j.gde.2017.03.006
  63. Yang D, Abdallah A, Li Z, et al. FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol. 2015;130(4):525–535. doi: 10.1007/s00401-015-1448-6
  64. Choi SY, Lopez-Gonzalez R, Krishnan G, et al. C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo. Nat Neurosci. 2019;22(6):851–862. doi: 10.1038/s41593-019-0397-0
  65. Wen X, Tan W, Westergard T, et al. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014;84(6):1213–25. doi: 10.1016/j.neuron.2014.12.010

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