Russian Journal of Genetics

, Volume 55, Issue 3, pp 271–277 | Cite as

DNA Methylation in Neurodegenerative Diseases

  • E. Yu. FedotovaEmail author
  • S. N. Illarioshkin


Epigenetic modifications in neurodegenerative diseases are just beginning to be studied; however, the growing interest in this phenomenon indicates its great importance in molecular mechanism of diseases and their phenotypical realization. DNA methylation takes one of the central places in gene expression regulation. This review considers the main DNA methylation types and the mechanisms of methylation and demethylation and provides general information on epigenetic regulation in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and hereditary ataxias. Possible prospects for targeted epigenetic correction as a new approach to neurodegenerative disease therapy are discussed.


neurodegenerative diseases epigenetics expression regulation DNA methylation 5-methyl cytosine 



This work was supported by the Russian Science Foundation (project no. 17-75-20211).


The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.


  1. 1.
    Bochkov, N.P., Ginter, E.K., and Puzyrev, V.P., Nasledstvennye bolezni: natsional’noe rukovodstvo (Hereditary Diseases: National Guideline), Moscow: GEOTAR-Media, 2012.Google Scholar
  2. 2.
    Allis, C.D., Jenuwein, T., Reinberg, D., and Caparos, M.L., Epigenetics, New York: Cold Spring Harbor Laboratory Press, 2007.Google Scholar
  3. 3.
    Landgrave-Gomez, J., Mercado-Gomez, O., and Guevara-Guzman, R., Epigenetic mechanisms in neurological and neurodegenerative diseases, Front. Cell Neurosci., 2015, vol. 9, p. 58. Google Scholar
  4. 4.
    Christopher, M.A., Kyle, S.M., and Katz, D.J., Neuroepigenetic mechanisms in disease, Epigenet. Chromatin, 2017, vol. 10, no. 1, p. 47. Google Scholar
  5. 5.
    Hwang, J.-Y., Aromolaran, K.A., and Zukin, R.S., The emerging field of epigenetics in neurodegeneration and neuroprotection, Nat. Rev. Neurosci., 2017, vol. 18, no. 6, pp. 347—361. Google Scholar
  6. 6.
    Fuso, A., The “golden age” of DNA methylation in neurodegenerative diseases, Clin. Chem. Lab. Med., 2013, vol. 51, no. 3, pp. 523—534. Google Scholar
  7. 7.
    Lardenoije, R., Iatrou, A., Kenis, G., et al., The epigenetics of aging and neurodegeneration, Prog. Neurobiol., 2015, vol. 131, pp. 21—64. Google Scholar
  8. 8.
    Jang, H.S., Shin, W.J., Lee, J.E., and Do, J.T., CpG and non-CpG methylation in epigenetic gene regulation and brain function, Genes (Basel), 2017, vol. 8, no. 6. pii. E148.
  9. 9.
    Qazi, T.J., Quan, Z., Mir, A., and Qing, H., Epigenetics in Alzheimer’s disease: perspective of DNA methylation, Mol. Neurobiol., 2018, vol. 55, no. 2, pp. 1026—1044. Google Scholar
  10. 10.
    Roubroeks, J.A.Y., Smith, R.G., van den Hove, D.L.A., and Lunnon, K., Epigenetics and DNA methylomic profiling in Alzheimer’s disease and other neurodegenerative disease, J. Neurochem., 2017, vol. 143, no. 2, pp. 158—170. Google Scholar
  11. 11.
    Corti, O., Lesage, S., and Brice, A., What genetics tells us about the causes and mechanisms of Parkinson’s disease, Physiol. Rev., 2011, vol. 91, pp. 1161—1218. Google Scholar
  12. 12.
    Stefanis, L., Synuclein in Parkinson’s disease, Cold Spring Harb. Perspect. Med., 2012, pp. 1—23.Google Scholar
  13. 13.
    Jowaed, A., Schmitt, I., Kaut, O., and Wullner, U., Methylation regulates alpha-synuclein expression and is decreased in Parkison’s disease patients’ brains, J. Neurosci., 2010, vol. 30, pp. 6355—6359. Google Scholar
  14. 14.
    Matsumoto, L., Takuma, H., Tamaoka, A., et al., CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease, PLoS One, 2010, vol. 11. e15522. Google Scholar
  15. 15.
    Ai, S.-X., Xu, Q., Hu, Y.-C., et al., Hypomethylation of SNCA in blood of patients with sporadic Parkinson’s disease, J. Neurol. Sci., 2014, vol. 337, pp. 123—128. Google Scholar
  16. 16.
    Pihlstom, L., Berge, V., Rengmark, A., and Toft, M., Parkinson’s disease correlates with promoter methylation in the α-synuclein gene, Mov. Disord., 2015, vol. 30, pp. 577—580. Google Scholar
  17. 17.
    Tan, Y.-Y., Wu, L., Zhao, Z.-B., et al., Methylation of α-synuclein and leucine-rich repeat kinase 2 in leukocyte DNA of Parkinson’s disease patients, Parkinsonism Relat. Disord., 2014, vol. 20, pp. 308—313. Google Scholar
  18. 18.
    Schmitt, I., Kaut, O., Khazneh, H., et al., L-dopa increases a-synuclein DNA methylation in Parkinson’s disease patients in vivo and in vitro, Mov. Disord., 2015, vol. 30, no. 13, pp. 1794—1801. Google Scholar
  19. 19.
    Masliah, E., Dumaop, W., Galasko, D., and Desplats, P., Distinctive patterns of DNA methylation associated with Parkinsons disease, Epigenetics, 2013, vol. 8, pp. 1030—1038. Google Scholar
  20. 20.
    Song, Y., Ding, H., Yang, J., et al., Pyrosequencing analysis of SNCA methylation levels in leukocytes from Parkinson’s disease patients, Neurosci. Lett., 2014, vol. 569, pp. 85—88. Google Scholar
  21. 21.
    Wuellner, U., Kaut, O., deBoni, L., et al., DNA methylation in Parkinson’s disease, J. Neurochem., 2016, vol. 139, suppl. 1, pp. 108—120. Google Scholar
  22. 22.
    Miranda-Morales, E., Meier, K., Sandoval-Carrillo, A., et al., Implication of DNA methylation in Parkinson’s disease, Front. Mol. Neurosci., 2017, vol. 10, p. 225. Google Scholar
  23. 23.
    De Mena, L., Cardo, L.F., Coto, E., et al., No differential DNA methylation of PARK2 in brain of Parkinson’s disease patients and healthy controls, Mov. Disord., 2013, vol. 28, pp. 2032—2033. Google Scholar
  24. 24.
    Pieper, H.C., Evert, B.O., Kaut, O., et al., Different methylation of the TNF-alpha promoter in cortex and substantia nigra: implications for selective neuronal vulnerability, Neurobiol. Dis., 2008, vol. 32, pp. 521—527. Google Scholar
  25. 25.
    Simon-Sanchez, J., Schulte, C., Bras, J.M., et al., Genome-wide association study reveals genetic risk underlying Parkinson’s disease, Nat. Genet., 2009, vol. 41, pp. 1308—1312. Google Scholar
  26. 26.
    Baker, M., Litvan, I., Houlden, H., et al., Association of an extended haplotype in the tau gene with progressive suprenuclear palsy, Hum. Mol. Genet., 1999, vol. 8, pp. 711—715.Google Scholar
  27. 27.
    Coupland, K.G., Mellick, G.D., Silburn, P.A., et al., DNA methylation of the MAPT gene in Parkinson’s disease cohort and modulation by vitamin E in vitro, Mov. Disord., 2014, vol. 29, pp. 1606—1614. Google Scholar
  28. 28.
    Moore, K., McKnight, A.J., Craig, D., and O’Neill, F., Epigenome-wide association study for Parkinson’s disease, Neuromol. Med., 2014, vol. 16, no. 4, pp. 845—855. Google Scholar
  29. 29.
    DeJesus-Hernandez, M., Mackenzie, I.R., and Boeve, B.F., Expanded GGGGCC hexanucleotide repeat in non-coding region of C9orf72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis, Neuron, 2011, vol. 72, pp. 245—256. Google Scholar
  30. 30.
    Woollacott, I.O.C. and Mead, S., The C9orf72 expansion mutation: gene structure, phenotypic and diagnostic issues, Acta Neuropathol., 2014, vol. 127, pp. 319—332. Google Scholar
  31. 31.
    Almeida, S., Gascon, E., and Tran, H., Modeling key pathological features of frontotemporal dementia with C9orf72 repeat expansion in iPSC-derived human neurons, Acta Neuropathol., 2013, vol. 126, pp. 385—399. Google Scholar
  32. 32.
    Yokoyama, J.S., Sirkes, D.W., and Miller, B.L., C9orf72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity, Am. J. Neurodegener. Dis., 2014, vol. 3, pp. 1—18.Google Scholar
  33. 33.
    Liu, E.Y., Russ, J., Wu, K., et al., C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD, Acta Neuropathol., 2014, vol. 128, pp. 525—541. Google Scholar
  34. 34.
    Dolinar, A., Ravnik-Glavac, M., and Glavac, D., Epigenetic mechanisms in amyotrophic lateral sclerosis: a short review, Mech. Ageing Dev., 2018, pii: S0047-6374(17)30225-7.
  35. 35.
    Russ, J., Liu, E.Y., Wu, K., et al., Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier, Acta Neuropathol., 2015, vol. 129, pp. 39–52.Google Scholar
  36. 36.
    Mcmillan, C.T., Russ, J., Wood, E.M., et al., C9orf72 promoter hypermenthylation is neuroprotective: neuroimaging and neuropathologic evidence, Neurology, 2015, vol. 84, pp. 1—9. Google Scholar
  37. 37.
    Cohen-Hadad, Y., Altarescu, G., Eldar-Geva, T., et al., Marked differences in C9orf72 methylation status and isoform expression between C9/ALS human embryonic and induced pluripotent stem cells, Stem Cell Rep., 2016, vol. 7, no. 5, pp. 927—940. Google Scholar
  38. 38.
    Belzil, V.V., Katzman, R.B., and Petrucelli, L., ALS and FTD: an epigenetic perspective, Acta Neuropathol., 2016, vol. 132, no. 4, pp. 487—502. doi.1007/s00401-016-1587-4Google Scholar
  39. 39.
    Delgado-Morales, R. and Esteller, M., Opening up the DNA methylome of dementia, Mol. Psychiatry, 2017, vol. 22, no. 4, pp. 485—496. Google Scholar
  40. 40.
    Evans-Galea, M.V., Hannan, A.J., Carrodus, N., et al., Epigenetic modifications in trinucleotide repeat disease, Trends Mol. Med., 2013, vol. 11, pp. 655—663. Google Scholar
  41. 41.
    Lee, J., Hwang, Y.J., Kim, K.Y., et al., Epigenetic mechanisms of neurodegeneration in Huntington’s disease, Neurotherapeutics, 2013, vol. 4, pp. 664—676. Google Scholar
  42. 42.
    Bai, G., Gheung, I., Shulha, H.P., et al., Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains, Hum. Mol. Genet., 2015, vol. 5, pp. 1441—1456. Google Scholar
  43. 43.
    Thomas, E.A., DNA methylation in Huntington’s disease: implications for transgenerational effects, Neurosci. Lett., 2016, vol. 625, pp. 34–39. Google Scholar
  44. 44.
    Nageshwaran, S. and Festenstein, R., Epigenetics and triplet-repeat neurological disease, Front. Neurol., 2015, vol. 6, p. 262. Google Scholar
  45. 45.
    Geschwind, D.H., Perlman, S., Fifueroa, C.P., et al., The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia, Am. J. Hum. Genet., 1997, vol. 60, pp. 842—850.Google Scholar
  46. 46.
    Ross, O.A., Rutherford, N.J., Baker, M., et al., Ataxin-2 repeat-length variation and neurodegeneration, Hum. Mol. Genet., 2011, vol. 20, pp. 3207—3212. Google Scholar
  47. 47.
    Laffita-Mesa, J.M., Bauer, P.O., Kouri, V., et al., Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications, Hum. Genet., 2012, vol. 131, pp. 625—638. Google Scholar
  48. 48.
    Schulz, J.B., Boesch, S., Burk, K., et al., Diagnosis and treatment of Friedreich ataxia: a European perspective, Nat. Rev. Neurol., 2009, vol. 5, pp. 222—234. Google Scholar
  49. 49.
    Santos, R., Lefevre, S., Sliwa, D., et al., Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities, Antioxid. Redox. Signal., 2010, vol. 13, pp. 651—690. Google Scholar
  50. 50.
    Filla, A., De Michele, G., Cavalcanti, F., et al., The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia, Am. J. Hum. Genet., 1996, vol. 59, pp. 554—560.Google Scholar
  51. 51.
    Illarioshkin, S.N., Bagieva, G.Kh., Klyushnikov, S.A., et al., Different phenotypes of Friedreich’s ataxia within one ‘pseudo-dominant’ genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features, Eur. J. Neurol., 2000, vol. 7, pp. 535—540.Google Scholar
  52. 52.
    Castaldo, I., Pinelli, M., Monticelli, A., et al., DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients, J. Med. Genet., 2008, vol. 45, pp. 808—812. Google Scholar
  53. 53.
    Evans-Galea, M.V., Carrodus, N., Rowley, S.M., et al., FXN methylation predicts expression and clinical outcome in Friedreich ataxia, Ann. Neurol., 2012, vol. 71, pp. 487—497. Google Scholar
  54. 54.
    Loesch, D. and Hagerman, R., Unstable mutations in the FMR1 gene and the phenotypes, Adv. Exp. Med. Biol., 2012, vol. 769, pp. 78—114.Google Scholar
  55. 55.
    Godler, D.E., Tassone, F., Loesch, D.Z., et al., Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio, Hum. Mol. Genet., 2010, vol. 19, pp. 1618—1632. Google Scholar
  56. 56.
    Godler, D.E., Slater, H.R., Bui, Q.M., et al., Fragile X Mental Retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleled: evidence from a pilot study, Clin. Chem., 2012, vol. 58, pp. 590—598. Google Scholar
  57. 57.
    Cornish, K.M., Kraan, C.M., Bui, Q.M., et al., Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women, Neurology, 2015, vol. 84, pp. 1—8. Google Scholar
  58. 58.
    Tabolacci, E., Moscato, U., Zalfe, F., et al., Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations, Eur. J. Hum. Genet., 2008, vol. 16, pp. 1487—1498. Google Scholar
  59. 59.
    Jin, P., Alisch, R.S., and Warren, S.T., RNA and microRNAs in fragile X mental retardation, Nat. Cell Biol., 2004, vol. 11, pp. 1048—1053.Google Scholar
  60. 60.
    Godler, D.E., Inaba, Y., Shi, E.Z., et al., Relationships between age and epi-genotype of the FMR1 exon 1/intron 1 boundary are consistent with non-random X-chromosome inactivation in FM individuals, with the selection for the unmethylated state being most significant between birth and puberty, Hum. Mol. Genet., 2013, vol. 22, pp. 1516—1524. Google Scholar
  61. 61.
    Colak, D., Zaninovic, N., Cohen, M., et al., Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome, Science, 2014, vol. 343, pp. 1002—1005. Google Scholar
  62. 62.
    Todd, P.K., Oh, S.Y., Krans, A., et al., Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome, PLoS Genet., 2010, vol. 12. e1001240. Google Scholar
  63. 63.
    de Esch, C.E., Ghazvini, M., Loos, F., et al., Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation, Stem Cell Rep., 2014, vol. 3, pp. 548—555. Google Scholar
  64. 64.
    Liu, X.S., Wu, H., Krzisch, M., et al., Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene, Cell, 2018, vol. 172, pp. 979—992. e6.

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  1. 1.Research Center of NeurologyMoscowRussia

Personalised recommendations