DNA methylation in Parkinson disease

Cover Page


Cite item

Full Text

Abstract

Parkinson disease (PD) is one of the most widespread neurodegenerative diseases in the elderly. It causes motor impairment and the development of non-motor symptoms, which reduce the quality of life and gradually lead to patient disability. However, PD pathogenesis remains unclear. Both genetic and environmental factors play a role in PD development. Recently, researchers have focused more on epigenetic mechanisms and their significance in multifactorial diseases. Epigenetic modifications lead to changes in gene expression and function without changing the DNA sequence. The main epigenetic mechanisms include histone modifications, non-coding RNA activity, and DNA methylation, with most studies of PD focusing on the methylation of various genes. Differential DNA methylation occurs mainly in gene regions important for transcription, contributing to either activation of expression (at low methylation levels) or suppression of gene activity (at hypermethylation). This review analyses most of the recent studies on DNA methylation, with an emphasis on analyzing genes whose participation in PD development has been confirmed in numerous research papers, specifically, the alpha-synuclein gene (SNCA) and the Tau protein gene (MAPT). The possible use of this analysis of the methylation level of various genes as biomarkers of PD is discussed, as well as the potential for future therapeutic strategies based on epigenetic modifications.

About the authors

Elena V. Yakovenko

Research Center of Neurology

Email: ekfedotova@gmail.com
Russian Federation, Moscow

Ekaterina Yu. Fedotova

Research Center of Neurology

Author for correspondence.
Email: ekfedotova@gmail.com
Russian Federation, Moscow

Sergey N. Illarioshkin

Research Center of Neurology

Email: ekfedotova@gmail.com
Russian Federation, Moscow

References

  1. Ozansoy M., Basak A.N. The central theme of Parkinson's disease: alpha-synuclein. Mol Neurobiol 2013; 47: 460–465. doi: 10.1007/s12035-012-8369-3. PMID: 23180276.
  2. Hirsc L., Jette N., Frolkis A. et al. The incidence of Parkinson's disease: a systematic review and meta‐analysis. Neuroepidemiology 2016; 46: 292–300. doi: 10.1159/000445751. PMID: 27105081.
  3. Karimi‐Moghadam A., Charsouei S., Bell B., Jabalameli M.R. Parkinson disease from mendelian forms to genetic susceptibility: new molecular insights into the neurodegeneration process. Cell Mol Neurobiol 2018; 38: 1153–1178. doi: 10.1007/s10571-018-0587-4. PMID: 29700661.
  4. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79: 368–376. doi: 10.1136/jnnp.2007.131045. PMID: 18344392.
  5. Kalia L.V., Kalia S.K., McLean P.J. et al. Alpha-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol 2013; 73: 155–169. doi: 10.1002/ana.23746. PMID: 23225525.
  6. Verstraeten A., Theuns J., Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet 2015; 31: 140–149. doi: 10.1016/j.tig.2015.01.004. PMID: 25703649.
  7. Nuytemans K., Theuns J., Cruts M., Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: A mutation update. Hum Mutat 2010; 31: 763–780. doi: 10.1002/humu.21277. PMID: 20506312.
  8. Desplats P., Patel P., Kosberg K. et al. Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis- related genes in mice models of Parkinson's disease. Mol Neurodegener 2012; 7: 49. doi: 10.1186/1750-1326-7-49. PMID: 23017109.
  9. Nalls M.A., Pankratz N., Lill C.M. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 2014; 46: 989–993. doi: 10.1038/ng.3043. PMID: 25064009.
  10. Nalls M.A., Blauwendraat C., Vallerga C.L. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol 2019; 18: 1091–1102. doi: 10.1016/S1474-4422(19)30320-5. PMID: 31701892.
  11. Waddington C.H. The epigenotype. 1942. Int J Epidemiol 2012; 41: 10–13. doi: 10.1093/ije/dyr184. PMID: 22186258.
  12. Portela A., Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057–1068. doi: 10.1038/nbt.1685. PMID: 20944598.
  13. Hamm C.A., Costa F.F. Epigenomes as therapeutic targets. Pharmacol Ther 2015; 151: 72–86. doi: 10.1016/j.pharmthera.2015.03.003. PMID: 25797698.
  14. Lardenoije R., Iatrou A., Kenis G. et al. The epigenetics of aging and neurodegeneration. Prog Neurobiol 2015; 131: 21–64. doi: 10.1016/j.pneurobio.2015.05.002. PMID: 26072273.
  15. Guo J.U., Ma D.K., Mo H. et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci 2011; 14: 1345–1351. doi: 10.1038/nn.2900. PMID: 21874013.
  16. Marques S.C.F., Oliveira C.R., Pereira C.M.F., Outeiro T.F. Epigenetics in neurodegeneration: a new layer of complexity. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 348–355. doi: 10.1016/j.pnpbp.2010.08.008. PMID: 20736041.
  17. Maze I., Noh K-M., Allis C.D. Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 2013; 38: 3–22. doi: 10.1038/npp.2012.124. PMID: 22828751.
  18. Coppede F. Genetics and epigenetics of Parkinson's disease. ScientificWorldJournal 2012; 2012: 489830. doi: 10.1100/2012/489830. PMID: 22623900.
  19. Johnson R., Noble W., Tartaglia G.G., Buckley N.J. Neurodegeneration as an RNA disorder. Prog Neurobiol 2012; 99: 293–315. doi: 10.1016/j.pneurobio.2012.09.006. PMID: 23063563.
  20. Singh A., Sen D. MicroRNAs in Parkinson's disease. Exp Brain Res 2017; 235: 2359–2374. doi: 10.1007/s00221-017-4989-1. PMID: 28526930.
  21. Patil V., Ward R.L., Hesson L.B. The evidence for functional non-CpG methylation in mammalian cells. Epigenetics 2014; 9: 823–828. doi: 10.4161/epi.28741. PMID: 24717538.
  22. Moore L.D., Le T., Fan G. DNA methylation and its basicfunction. Neuropsychopharmacology 2013; 38: 23–38.doi: 10.1038/npp.2012.112. PMID: 22781841.
  23. Jurkowska R.Z., Jurkowski T.P., Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem 2011; 12: 206–222. doi: 10.1002/cbic.201000195. PMID: 21243710.
  24. Li Y., Liu Y., Strickland F.M., Richardson B. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 2010; 45: 312–322. doi: 10.1016/j.exger.2009.12.008. PMID: 20035856.
  25. Feng Y., Jankovic J., Wu Y-C. Epigenetic mechanisms in Parkinson's disease. J Neurol Sci 2015; 349: 3–9. doi: 10.1016/j.jns.2014.12.017. PMID: 25553963.
  26. Pastor W.A., Aravind L., Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 2013; 14: 341–356. doi: 10.1038/nrm3589. PMID: 23698584.
  27. Maroteaux L., Campanelli J.T., Scheller R.H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 1988; 8: 2804–2815. doi: 10.1523/JNEUROSCI.08-08-02804.1988. PMID: 3411354.
  28. Polymeropoulos M.H., Lavedan C., Leroy E. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045–2047. doi: 10.1126/science.276.5321.2045. PMID: 9197268.
  29. Kruger R., Vieira-Saecker A.M., Kuhn W. et al. Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol1999; 45: 611-617. doi: 10.1002/1531-8249(199905)45:5<611::aid-ana9>3.0.co;2-x. PMID: 10319883.
  30. Zarranz J.J., Alegre J., Gomez-Esteban J.C. et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55: 164–173. doi: 10.1002/ana.10795. PMID: 14755719.
  31. Gallegos S., Pacheco C., Peters C. et al. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease. Front Neurosci 2015; 9: 59. doi: 10.3389/fnins.2015.00059. PMID: 25805964.
  32. Chartier-Harlin M-C., Kachergus J., Roumier C. et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004; 364: 1167–1169. doi: 10.1016/S0140-6736(04)17103-1. PMID: 15451224.
  33. Singleton A.B., Farrer M., Johnson J. et al. Alpha-Synuclein locus triplication causes Parkinson's disease. Science 2003; 302: 841. doi: 10.1126/science.1090278. PMID: 14593171.
  34. Miller D.W., Hague S.M., Clarimon J. et al. Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 2004; 62: 1835–1838. doi: 10.1212/01.wnl.0000127517.33208.f4. PMID: 15159488.
  35. Jowaed A., Schmitt I., Kaut O., Wullner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 2010; 30: 6355–6359. doi: 10.1523/JNEUROSCI.6119-09.2010. PMID: 20445061.
  36. 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; 5: e15522. doi: 10.1371/journal.pone.0015522. PMID: 21124796.
  37. Ai S., Xu Q., Hu Y. et al. Hypomethylation of SNCA in blood of patients with sporadic Parkinson's disease. J Neurol Sci 2014; 337: 123–128. doi: 10.1016/j.jns.2013.11.033. PMID: 24326201.
  38. Pihlstrom L., Berge V., Rengmark A., Toft M. Parkinson's disease correlates with promoter methylation in the alpha-synuclein gene. Mov Disord 2015; 30: 577–580. doi: 10.1002/mds.26073. PMID: 25545759.
  39. 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; 30: 1794–1801. doi: 10.1002/mds.26319. PMID: 26173746.
  40. Richter J., Appenzeller S., Ammerpohl O. et al. No evidence for differential methylation of alpha-synuclein in leukocyte DNA of Parkinson's disease patients. Mov Disord 2012; 27: 590–591. doi: 10.1002/mds.24907. PMID: 22262231.
  41. Song Y., Ding H., Yang J. et al. Pyrosequencing analysis of SNCA methylation levels in leukocytes from Parkinson's disease patients. Neurosci Lett 2014; 569: 85–88. doi: 10.1016/j.neulet.2014.03.076. PMID: 24721670.
  42. Guhathakurta S., Evangelista B.A., Ghosh S. et al. Hypomethylation of intron1 of α-synuclein gene does not correlate with Parkinson's disease. Mol Brain 2017; 10: 6. doi: 10.1186/s13041-017-0285-z. PMID: 28173842.
  43. Funahashi Y., Yoshino Y., Yamazaki K. et al. DNA methylation changes at SNCA intron 1 in patients with dementia with Lewy bodies. Psychiatry Clin Neurosci 2017; 71: 28–35. doi: 10.1111/pcn.12462. PMID: 27685250.
  44. de Boni L., Tierling S., Roeber S. et al. Next-generation sequencing reveals regional differences of the alpha-synuclein methylation state independent of Lewy body disease. Neuromolecular Med 2011; 13: 310–320. doi: 10.1007/s12017-011-8163-9. PMID: 22042430.
  45. Desplats P., Spencer B., Coffee E. et al. Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem 2011; 286: 9031–9037. doi: 10.1074/jbc.C110.212589. PMID: 21296890.
  46. Eryilmaz I.E., Cecener G., Erer S. et al. Epigenetic approach to early-onset Parkinson's disease: lowmethylation status of SNCA and PARK2 promoter regions. Neurol Res 2017; 39: 965–972. doi: 10.1080/01616412.2017.1368141. PMID: 28830306.
  47. Tan Y., Wu L., Zhao Z. et al. Methylation of alpha-synuclein and leucine-rich repeat kinase 2 in leukocyte DNA of Parkinson's disease patients. Parkinsonism Relat Disord 2014; 20: 308–313. doi: 10.1016/j.parkreldis.2013.12.002. PMID: 24398085.
  48. Navarro-Sánchez L, Águeda-Gómez B., Aparicio S., Pérez-Tur J. Epigenetic study in Parkinson's disease: a pilot analysis of DNA methylation in candidate genes in brain. Cells 2018; 7: 150. doi: 10.3390/cells7100150. PMID: 30261625.
  49. Tan Y., Wu L., Li D. et al. Methylation status of DJ-1 in leukocyte DNA of Parkinson’s disease patients. Transl Neurodegener2016; 5: 5. doi: 10.1186/s40035-016-0052-6. PMID: 27034775.
  50. Simón-Sánchez J., Schulte C., Bras J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41: 1308–1312. doi: 10.1038/ng.487. PMID: 19915575.
  51. Kwok J.B.J., Teber E.T., Loy C. et al. Tau haplotypes regulate transcription and are associated with Parkinson’s disease. Ann Neurol 2004; 55: 329–334. doi: 10.1002/ana.10826. PMID: 14991810.
  52. Coupland K.G., Mellick G.D., Silburn P.A. et al. DNA methylation of the MAPT gene in Parkinson’s disease cohorts and modulation by vitamin E in vitro. Mov Disord 2014; 29: 1606–1614. doi: 10.1002/mds.25784. PMID: 24375821.
  53. 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; 32: 521–527. doi: 10.1016/j.nbd.2008.09.010. PMID: 18930140.
  54. Lin Q., Ding H., Zheng Z. et al. Promoter methylation analysis of seven clock genes in Parkinson’s disease. Neurosci Lett 2012; 507: 147–150. doi: 10.1016/j.neulet.2011.12.007. PMID: 22193177.
  55. Su X., Chu Y., Kordower J.H. et al. PGC-1α promoter methylation in Parkinson’s disease. PLoS One 2015; 28; 10: e0134087. doi: 10.1371/journal.pone.0134087. PMID: 26317511.
  56. Masliah E., Dumaop W., Galasko D., Desplats P. Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 2013; 8: 1030–1038. doi: 10.4161/epi.25865. PMID: 23907097.
  57. Wang C., Chen L., Yang Y. et al. Identification of potential bloodbiomarkers for Parkinson's disease by gene expression and DNA methylation dataintegration analysis. Clin Epigenetics 2019; 11: 24. doi: 10.1186/s13148-019-0621-5. PMID: 30744671.
  58. Young J.I., Sivasankaran S.K., Wang L. et al. Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease. Neurol Genet 2019; 5: e342. doi: 10.1212/NXG.0000000000000342. PMID: 31403079.
  59. Kaut O., Schmitt I., Tost J. et al. Epigenome-wide DNA methylation analysis in siblings andmonozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells. Neurogenetics 2017; 18: 7–22. doi: 10.1007/s10048-016-0497-x. PMID: 27709425.
  60. Obeid R., Schadt A., Dillmann U. et al. Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem 2009; 55: 1852–1860. doi: 10.1373/clinchem.2009.125021. PMID: 19679632.
  61. Konsoula Z., Barile F.A. Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods 2012; 66: 215–220. doi: 10.1016/j.vascn.2012.08.001. PMID: 22902970.
  62. Xu Z., Li H., Jin P. Epigenetics-based therapeutics for neurodegenerative disorders. Curr Transl Geriatr Exp Gerontol Rep 2012; 1: 229–236. doi: 10.1007/s13670-012-0027-0. PMID: 23526405.
  63. Narayan P., Dragunow M. Pharmacology of epigenetics in brain disorders. Br J Pharmacol 2010; 159: 285–303. doi: 10.1111/j.1476-5381.2009.00526.x. PMID: 20015091.
  64. Kantor B., Tagliafierro L., Gu J. Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: a potential strategy for precision therapy in PD. Mol Ther 2018; 26: 2638–2649. doi: 10.1016/j.ymthe.2018.08.019. PMID: 30266652.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2020 Yakovenko E.V., Fedotova E.Y., Illarioshkin S.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies