Advertisement

Neurotherapeutics

, Volume 15, Issue 1, pp 156–175 | Cite as

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

  • Jin Gao
  • Catherine M. Cahill
  • Xudong Huang
  • Joshua L. Roffman
  • Stefania Lamon-Fava
  • Maurizio Fava
  • David Mischoulon
  • Jack T. Rogers
Current Perspectives

Abstract

S-Adenosyl methionine (SAMe), as a major methyl donor, exerts its influence on central nervous system function through cellular transmethylation pathways, including the methylation of DNA, histones, protein phosphatase 2A, and several catecholamine moieties. Based on available evidence, this review focuses on the lifelong range of severe neuropsychiatric and neurodegenerative diseases and their associated neuropathologies, which have been linked to the deficiency/load of SAMe production or/and the disturbance in transmethylation pathways. Also included in this review are the present-day applications of SAMe in the treatment in these diseases in each age group.

Keywords

S-Adenosyl-methionine Transmethylation Pathway Psychiatric disease Neurodegenerative disease 

Notes

Acknowledgements

Dr. Jin Gao was supported by the grant from National Natural Science Foundation of China (http://www.nsfc.gov.cn, No:81501170) Dr. Jack Rogers is supported by 5R01MH102279-03 (M. Fava, MGH), and was a recipient of The Zenith Fellows Award of Alzheimer’s Association and of a National Institutes of Health grant (R21NS077079-01A1). Dr. Xudong Huang and JTR are supported by a National Institutes of Health grant (1R01AG056614-01).

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2017_593_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1239 kb)

References

  1. 1.
    Cantoni GL. Biological methylation: selected aspects. Annu Rev Biochem. 1975;44:435-451.CrossRefPubMedGoogle Scholar
  2. 2.
    Mato JM, Alvarez L, Ortiz P, et al. S-Adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol Ther. 1997;73(3):265-280.CrossRefPubMedGoogle Scholar
  3. 3.
    Giulidori P, Galli-kienle M, Catto E, et al. Transmethylation, transsulfuration, and aminopropylation reactions of S-adenosyl-l-methionine in vivo. J Biol Chem. 1984;259(7):4205-4211.PubMedGoogle Scholar
  4. 4.
    Lu SC. S-Adenosylmethionine. Int J Biochem Cell Biol. 2000;32(4):391-395.CrossRefPubMedGoogle Scholar
  5. 5.
    Teh AL, Pan H, Chen L, et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 2014;24(7):1064-1074.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Fuso A, Seminara L, Cavallaro RA, et al. S-Adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and bace and beta-amyloid production. Mol Cell Neurosci. 2005;28(1):195-204.CrossRefPubMedGoogle Scholar
  7. 7.
    Panza F, Frisardi V, Capurso C, et al. Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimer's disease: a review. Scientificworldjournal. 2009;9:373-389.CrossRefPubMedGoogle Scholar
  8. 8.
    De Berardis D, Orsolini L, Serroni N, et al. A comprehensive review on the efficacy of S-adenosyl-L-methionine in major depressive disorder. Cns Neurol Disord Drug Targets. 2016;15(1):35-44.CrossRefPubMedGoogle Scholar
  9. 9.
    Bottiglieri T. Folate, vitamin B(1)(2), and S-adenosylmethionine. Psychiatr Clin North Am. 2013;36(1):1-13.CrossRefPubMedGoogle Scholar
  10. 10.
    Mentch SJ, Locasale JW. One-carbon metabolism and epigenetics: understanding the specificity. Ann N Y Acad Sci. 2016;1363:91-98.CrossRefPubMedGoogle Scholar
  11. 11.
    Mato JM, Corrales FJ, Lu SC, et al. S-adenosylmethionine: a control switch that regulates liver function. FASEB J. 2002;16(1):15-26.CrossRefPubMedGoogle Scholar
  12. 12.
    Jarrett JT, Huang S, Matthews RG. Methionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin. Biochemistry. 1998;37(16):5372-5382.CrossRefPubMedGoogle Scholar
  13. 13.
    Gueant JL, Caillerez-Fofou M, Battaglia-Hsu S, et al. Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase. Biochimie. 2013;95(5):1033-1040.CrossRefPubMedGoogle Scholar
  14. 14.
    Gherasim C, Lofgren M, Banerjee R. Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin. J Biol Chem. 2013;288(19):13186-13193.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949-960.CrossRefPubMedGoogle Scholar
  16. 16.
    Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a huge review. Am J Epidemiol. 2004;159(5):423-443.CrossRefPubMedGoogle Scholar
  17. 17.
    Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533(1):11-20.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim JM, Stewart R, Kim SW, et al. Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry. 2008;192(4):268-274.CrossRefPubMedGoogle Scholar
  19. 19.
    Fava M, Borus JS, Alpert JE, et al. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry. 1997;154(3):426-428.CrossRefPubMedGoogle Scholar
  20. 20.
    Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, pART 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004;65(8):1090-1095.CrossRefPubMedGoogle Scholar
  21. 21.
    Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-1783.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Kennedy DO. B vitamins and the brain: mechanisms, dose and efficacy—a review. Nutrients. 2016;8(2):68.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Ankar A, Bhimji SS. Vitamin, B12 (cobalamin), deficiency. Treasure Island (FL): StatPearls Publishing; 2017.Google Scholar
  24. 24.
    Kumar N. Neurologic aspects of cobalamin (B12) deficiency. Handb Clin Neurol. 2014;120:915-926.CrossRefPubMedGoogle Scholar
  25. 25.
    Yi P, Melnyk S, Pogribna M, et al. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem. 2000;275(38):29318-2923.CrossRefPubMedGoogle Scholar
  26. 26.
    Fernandez-Roig S, Lai SC, Murphy MM, et al. Vitamin B12 deficiency in the brain leads to dna hypomethylation in the TCBLR/CD320 knockout mouse. Nutr Metab (Lond). 2012;9:41.Google Scholar
  27. 27.
    Tanaka H. [Old or new medicine? Vitamin B12 and peripheral nerve neuropathy]. Brain Nerve. 2013;65(9):1077-1082.PubMedGoogle Scholar
  28. 28.
    Zhang Y, Hodgson NW, Trivedi MS, et al. Decreased brain levels of vitamin B12 in aging, autism and schizophrenia. PLOS ONE. 2016;11(1):E0146797.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Loenen WA. S-Adenosylmethionine: jack of all trades and master of everything? Biochem Soc Trans. 2006;34(PT 2):330-333.CrossRefPubMedGoogle Scholar
  30. 30.
    Martinez-Lopez N, Varela-Rey M, Ariz U, et al. S-adenosylmethionine and proliferation: new pathways, new targets. Biochem Soc Trans. 2008;36(PT 5):848-852.CrossRefPubMedGoogle Scholar
  31. 31.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl.):245-254.CrossRefPubMedGoogle Scholar
  32. 32.
    Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293(5532):1089-1093.CrossRefPubMedGoogle Scholar
  33. 33.
    Xie W, Barr CL, Kim A, ET AL. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell. 2012;148(4):816-831.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Fernando HJ, Mammarella MC, Grandoni G, et al. Forecasting PM10 in metropolitan areas: efficacy of neural networks. Environ Pollut. 2012;163:62-67.CrossRefPubMedGoogle Scholar
  35. 35.
    Lister R, Mukamel EA, Nery JR, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341(6146):1237905.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Smith ZD, Chan MM, Mikkelsen TS, et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012;484(7394):339-344.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Varley KE, Gertz J, Bowling KM, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013;23(3):555-567.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Guo JU, Su Y, Shin JH, et al. Distribution, recognition and regulation of non-CPG methylation in the adult mammalian brain. Nat Neurosci. 2014;17(2):215-222.CrossRefPubMedGoogle Scholar
  39. 39.
    Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930-935.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Yu M, Hon GC, Szulwach KE, et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell. 2012;149(6):1368-1380.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Song CX, Szulwach KE, Fu Y, et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol. 2011;29(1):68-72.CrossRefPubMedGoogle Scholar
  42. 42.
    Khare T, Pai S, Koncevicius K, et al. 5-HMC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nat Struct Mol Biol. 2012;19(10):1037-1043.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Guo JU, Su Y, Zhong C, et al. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011;145(3):423-434.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Okano M, Bell DW, Haber DA, et al. DNA methyltransferases DNMT3A and DNMT3B are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247-257.CrossRefPubMedGoogle Scholar
  45. 45.
    Rhee I, Jair KW, Yen RW, et al. CPG methylation is maintained in human cancer cells lacking DNMT1. Nature. 2000;404(6781):1003-1007.CrossRefPubMedGoogle Scholar
  46. 46.
    Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet. 2000;9(16):2395-2402.CrossRefPubMedGoogle Scholar
  47. 47.
    Suetake I, Miyazaki J, Murakami C, et al. Distinct enzymatic properties of recombinant mouse DNA methyltransferases DNMT3A and DNMT3B. J Biochem. 2003;133(6):737-744.CrossRefPubMedGoogle Scholar
  48. 48.
    Gros C, CHauvigne L, Poulet A, et al. Development of a universal radioactive DNA methyltransferase inhibition test for high-throughput screening and mechanistic studies. Nucleic Acids Res. 2013;41(19):E185.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Feng J, Chang H, Li E, et al. Dynamic expression of de novo DNA methyltransferases DNMT3A and DNMT3B in the central nervous system. J Neurosci Res. 2005;79(6):734-746.CrossRefPubMedGoogle Scholar
  50. 50.
    Watanabe D, Uchiyama K, Hanaoka K. Transition of mouse de novo methyltransferases expression from DNMT3B to DNMT3A during neural progenitor cell development. Neuroscience. 2006;142(3):727-737.CrossRefPubMedGoogle Scholar
  51. 51.
    Ito S, D'Alessio AC, Taranova OV, et al. Role of TET proteins in 5MC to 5HMC conversion, ES-celL self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129-1133.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Zhang RR, Cui QY, Murai K, et al. TET1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell. 2013;13(2):237-245.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Li X, Wei W, Zhao QY, et al. Neocortical TET3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci U S A. 2014;111(19):7120-7125.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Yu H, Su Y, Shin J, et al. TET3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat Neurosci. 2015;18(6):836-843.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Nan X, Meehan RR, Bird A. Dissection of the methyl-CPG binding domain from the chromosomal protein MECP2. Nucleic Acids Res. 1993;21(21):4886-4892.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Skene PJ, Illingworth RS, Webb S, et al. Neuronal MECP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell. 2010;37(4):457-468.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Shahbazian MD, Antalffy B, Armstrong DL, et al. Insight into Rett syndrome: MECP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11(2):115-124.CrossRefPubMedGoogle Scholar
  58. 58.
    Nan X, Campoy FJ, Bird A. MECP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88(4):471-481.CrossRefPubMedGoogle Scholar
  59. 59.
    Lyst MJ, Ekiert R, Ebert DH, et al. Rett syndrome mutations abolish the interaction of MECP2 with the NCOR/SMRT co-repressor. Nat Neurosci. 2013;16(7):898-902.CrossRefPubMedGoogle Scholar
  60. 60.
    Kinde B, Gabel HW, Gilbert CS, et al. Reading the unique DNA methylation landscape of the brain: non-CpG methylation, hydroxymethylation, and MECP2. Proc Natl Acad SCI U S A. 2015;112(22):6800-6806.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Gabel HW, Kinde B, Stroud H, et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 2015;522(7554):89-93.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Chen L, Chen K, Lavery LA, et al. MECP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett Syndrome. Proc Natl Acad Sci U S A. 2015;112(17):5509-5514.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23-38.CrossRefPubMedGoogle Scholar
  64. 64.
    Fan G, Martinowich K, Chin MH, et al. DNA methylation controls the timing of astrogliogenesis through regulation of Jak-STAT signaling. Development. 2005;132(15):3345-3356.CrossRefPubMedGoogle Scholar
  65. 65.
    Oda M, Oxley D, Dean W, et al. Regulation of lineage specific DNA hypomethylation in mouse trophectoderm. PLOS ONE. 2013;8(6):E68846.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Chen CC, Wang KY, Shen CK. DNA 5-Methylcytosine demethylation activities of the mammalian DNA methyltransferases. J Biol Chem. 2013;288(13):9084-9091.PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Van Der Wijst MG, Venkiteswaran M, Chen H, et al. Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase. Epigenetics. 2015;10(8):671-676.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Varela-Rey M, Iruarrizaga-Lejarreta M, Lozano JJ, et al. S-adenosylmethionine levels regulate the Schwann cell DNA methylome. Neuron. 2014;81(5):1024-1039.PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Guo JU, Ma DK, Mo H, et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci. 2011;14(10):1345-1351.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Mcgowan PO, Sasaki A, D'Alessio AC, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12(3):342-348.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Saunderson EA, Spiers H, Mifsud KR, et al. Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. Proc Natl Acad Sci U S A. 2016;113(17):4830-4835.PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Sutter BM, Wu X, Laxman S, et al. Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell. 2013;154(2):403-415.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Nguyen S, Meletis K, Fu D, et al. Ablation of de novo dna methyltransferase DNMT3A in the nervous system leads to neuromuscular defects and shortened lifespan. Dev Dyn. 2007;236(6):1663-1676.CrossRefPubMedGoogle Scholar
  74. 74.
    Golshani P, Hutnick L, Schweizer F, et al. Conditional DNMT1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation. Thalamus Relat Syst. 2005;3(3):227-233.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Santiago M, Antunes C, Guedes M, et al. TET enzymes and DNA hydroxymethylation in neural development and function - how critical are they? Genomics. 2014;104(5):334-340.CrossRefPubMedGoogle Scholar
  76. 76.
    Shojaei Saadi HA, Gagne D, Fournier E, et al. Responses of bovine early embryos to S-adenosyl methionine supplementation in culture. Epigenomics. 2016;8(8):1039-1060.CrossRefPubMedGoogle Scholar
  77. 77.
    Feng J, Fan G. The role of DNA methylation in the central nervous system and neuropsychiatric disorders. Int Rev Neurobiol. 2009;89:67-84.CrossRefPubMedGoogle Scholar
  78. 78.
    Molloy AM, Kirke PN, Troendle JF, et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics. 2009;123(3):917-923.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Ratan SK, Rattan KN, Pandey RM, et al. Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatr Surg Int. 2008;24(7):803-808.CrossRefPubMedGoogle Scholar
  80. 80.
    Czeizel AE. Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2009;85(4):260-268.CrossRefPubMedGoogle Scholar
  81. 81.
    Czeizel AE, Dudas I, Paput L, et al. Prevention of neural-tube defects with periconceptional folic acid, methylfolate, or multivitamins? Ann Nutr Metab. 2011;58(4):263-71.CrossRefPubMedGoogle Scholar
  82. 82.
    Wilson RD, Audibert F, Brock JA, et al. Pre-conception folic acid and multivitamin supplementation for the primary and secondary prevention of neural tube defects and other folic acid-sensitive congenital anomalies. J Obstet Gynaecol Can. 2015;37(6):534-552.CrossRefPubMedGoogle Scholar
  83. 83.
    Coelho CN, Klein NW. Methionine and neural tube closure in cultured rat embryos: morphological and biochemical analyses. Teratology. 1990;42(4):437-451.CrossRefPubMedGoogle Scholar
  84. 84.
    Dunlevy LP, Burren KA, Chitty LS, et al. Excess methionine suppresses the methylation cycle and inhibits neural tube closure in mouse embryos. FEBS Lett. 2006;580(11):2803-2807.CrossRefPubMedGoogle Scholar
  85. 85.
    Afman LA, Blom HJ, Drittij MJ, et al. Inhibition of transmethylation disturbs neurulation in chick embryos. Brain Res Dev Brain Res. 2005;158(1-2):59-65.CrossRefPubMedGoogle Scholar
  86. 86.
    Olthof MR, Van Vliet T, Boelsma E, et al. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr. 2003;133(12):4135-4138.CrossRefPubMedGoogle Scholar
  87. 87.
    Wang X, Guan Z, Chen Y, et al. Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism. PLOS ONE. 2015;10(3):E0121869.PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLOS ONE. 2009;4(11):E7845.PubMedCentralCrossRefPubMedGoogle Scholar
  89. 89.
    Amir RE, Van Den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-188.CrossRefPubMedGoogle Scholar
  90. 90.
    Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950.PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Guy J, Hendrich B, Holmes M, et al. A mouse MECP2-null mutation causes neurological symptoms that mimic rett syndrome. Nat Genet. 2001;27(3):322-326.CrossRefPubMedGoogle Scholar
  92. 92.
    Kaludov NK, Wolffe AP. MECP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res. 2000;28(9):1921-1928.PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Glaze DG, Percy AK, Motil KJ, et al. A study of the treatment of Rett syndrome with folate and betaine. J Child Neurol. 2009;24(5):551-556.PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Hagebeuk EE, Koelman JH, Duran M, et al. Clinical and electroencephalographic effects of folinic acid treatment in Rett syndrome patients. J Child Neurol. 2011;26(6):718-723.CrossRefPubMedGoogle Scholar
  95. 95.
    Hagebeuk EE, Duran M, Koelman JH, et al. folinic acid supplementation in Rett syndrome patients does not influence the course of the disease: a randomized study. J Child Neurol. 2012;27(3):304-309.CrossRefPubMedGoogle Scholar
  96. 96.
    Hagebeuk EE, Duran M, Abeling NG, et al. S-Adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation. J Inherit Metab Dis. 2013;36(6):967-972.CrossRefPubMedGoogle Scholar
  97. 97.
    Yu XF, Li M, Zheng Y. [Association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a meta analysis]. Zhongguo Dang Dai Er Ke Za Zhi. 2017;19(3):286-291.PubMedGoogle Scholar
  98. 98.
    Pogribna M, Melnyk S, Pogribny I, et al. homocysteine metabolism in children with DOWN syndrome: in vitro modulation. Am J Hum Genet. 2001;69(1):88-95.PubMedCentralCrossRefPubMedGoogle Scholar
  99. 99.
    Obeid R, Hubner U, Bodis M, et al. Plasma amyloid beta 1-42 and DNA methylation pattern predict accelerated aging in young subjects with Down syndrome. Neuromolecular Med. 2016;18(4):593-601.CrossRefPubMedGoogle Scholar
  100. 100.
    Obeid R, Hartmuth K, Herrmann W, et al. Blood Biomarkers of methylation in down syndrome and metabolic simulations using a mathematical model. Mol Nutr Food Res. 2012;56(10):1582-1589.CrossRefPubMedGoogle Scholar
  101. 101.
    Fountoulakis M, Gulesserian T, Lubec G. Overexpression of c1-tetrahydrofolate synthase in fetal down syndrome brain. J Neural TRansm Suppl. 2003(67):85-93.CrossRefGoogle Scholar
  102. 102.
    Song C, He J, Chen J, et al. Effect of the onecarbon unit cycle on overall dna methylation in children with down's syndrome. Mol Med Rep. 2015;12(6):8209-8214.CrossRefPubMedGoogle Scholar
  103. 103.
    Infantino V, Castegna A, Iacobazzi F, et al. Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in down's syndrome. Mol Genet Metab. 2011;102(3):378-382.CrossRefPubMedGoogle Scholar
  104. 104.
    Beetstra S, Thomas P, Salisbury C, et al. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei. MUTAT RES. 2005;578(1-2):317-326.CrossRefPubMedGoogle Scholar
  105. 105.
    Da Silva LR, Vergani N, Galdieri Lde C, et al. Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for down syndrome in brazil. Am J Med Genet A. 2005;135(3):263-267.CrossRefPubMedGoogle Scholar
  106. 106.
    Biselli JM, Goloni-Bertollo EM, Zampieri BL, et al. Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for down syndrome in brazil. Genet Mol Res. 2008;7(1):33-42.CrossRefPubMedGoogle Scholar
  107. 107.
    Smythies JR. Biochemistry of schizophrenia. Postgrad Med J. 1963;39:26-33.PubMedCentralCrossRefPubMedGoogle Scholar
  108. 108.
    Kelsoe JR, Tolbert LC, Crews EL, et al. Kinetic evidence for decreased methionine adenosyltransferase activity in erythrocytes from schizophrenics. J Neurosci Res. 1982;8(1):99-103.CrossRefPubMedGoogle Scholar
  109. 109.
    Muntjewerff JW, Van Der Put N, Eskes T, et al. Homocysteine metabolism and b-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Res. 2003;121(1):1-9.CrossRefPubMedGoogle Scholar
  110. 110.
    Garcia-Miss Mdel R, Perez-Mutul J, Lopez-Canul B, et al. Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T Polymorphism, are risk factors for schizophrenia. J Psychiatr Res. 2010;44(7):441-446.CrossRefPubMedGoogle Scholar
  111. 111.
    Brown AS, Bottiglieri T, Schaefer CA, et al. Elevated prenatal homocysteine levels as a risk factor for schizophrenia. Arch Gen Psychiatry. 2007;64(1):31-39.CrossRefPubMedGoogle Scholar
  112. 112.
    Kumar KS, Govindaiah V, Naushad SE, et al. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss. J Obstet Gynaecol. 2003;23(1):55-58.CrossRefPubMedGoogle Scholar
  113. 113.
    Picker JD, Coyle JT. Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia? Harv Rev Psychiatry. 2005;13(4):197-205.CrossRefPubMedGoogle Scholar
  114. 114.
    Kirkbride JB, Susser E, Kundakovic M, et al. Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects? Epigenomics. 2012;4(3):303-315.PubMedCentralCrossRefPubMedGoogle Scholar
  115. 115.
    Szyf M. Epigenetics, a key for unlocking complex cns disorders? therapeutic implications. Eur Neuropsychopharmacol. 2015;25(5):682-702.CrossRefPubMedGoogle Scholar
  116. 116.
    Veldic M, Guidotti A, Maloku E, et al. In psychosis, cortical interneurons overexpress dna-methyltransferase 1. Proc Natl Acad Sci U S A. 2005;102(6):2152-2157.PubMedCentralCrossRefPubMedGoogle Scholar
  117. 117.
    Zhubi A, Veldic M, Puri NV, et al. An upregulation of dna-methyltransferase 1 and 3A expressed in telencephalic gabaergic neurons of schizophrenia patients is also detected in peripheral blood Lymphocytes. Schizophr Res. 2009;111(1-3):115-122.PubMedCentralCrossRefPubMedGoogle Scholar
  118. 118.
    Chen Y, Sharma RP, Costa RH, et al. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res. 2002;30(13):2930-2939.PubMedCentralCrossRefPubMedGoogle Scholar
  119. 119.
    Abdolmaleky HM, Cheng KH, Russo A, et al. Hypermethylation of the reelin (reln) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005;134B(1):60-66.CrossRefPubMedGoogle Scholar
  120. 120.
    Grayson DR, Jia X, Chen Y, et al. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A. 2005;102(26):9341-9346.PubMedCentralCrossRefPubMedGoogle Scholar
  121. 121.
    Veldic M, Caruncho HJ, Liu WS, et al. DNA-Methyltransferase 1 MRNA is selectively overexpressed in telencephalic gabaergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A. 2004;101(1):348-353.CrossRefPubMedGoogle Scholar
  122. 122.
    Abdolmaleky HM, Cheng KH, Faraone SV, et al. Hypomethylation of mb-comt promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006;15(21):3132-3145.PubMedCentralCrossRefPubMedGoogle Scholar
  123. 123.
    Nohesara S, Ghadirivasfi M, Mostafavi S, et al. DNA Hypomethylation of MB-COMT Promoter in the dna derived from saliva in schizophrenia and bipolar disorder. J Psychiatr Res. 2011;45(11):1432-1438.CrossRefPubMedGoogle Scholar
  124. 124.
    Rosa A, Peralta V, Cuesta MJ, et al. New evidence of association between comt gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. Am J Psychiatry. 2004;161(6):1110-1112.CrossRefPubMedGoogle Scholar
  125. 125.
    Grayson DR, Chen Y, Dong E, et al. From Trans-Methylation To Cytosine Methylation: Evolution Of The Methylation Hypothesis Of Schizophrenia. Epigenetics. 2009;4(3):144-149.CrossRefPubMedGoogle Scholar
  126. 126.
    Tremolizzo L, Carboni G, Ruzicka WB, et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci U S A. 2002;99(26):17095-17100.PubMedCentralCrossRefPubMedGoogle Scholar
  127. 127.
    Levine J, Stahl Z, Sela BA, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry. 2006;60(3):265-269.CrossRefPubMedGoogle Scholar
  128. 128.
    Hill M, Shannahan K, Jasinski S, et al. Folate Supplementation in schizophrenia: a possible role for mthfr genotype. Schizophr Res. 2011;127(1-3):41-45.CrossRefPubMedGoogle Scholar
  129. 129.
    Roffman JL, Lamberti JS, Achtyes E, et al. Randomized multicenter investigation of folate plus vitamin B12 Supplementation in Schizophrenia. JAMA Psychiatry. 2013;70(5):481-489.PubMedCentralCrossRefPubMedGoogle Scholar
  130. 130.
    Procter A. Enhancement of recovery from psychiatric illness by methylfolate. BR J Psychiatry. 1991;159:271-272.CrossRefPubMedGoogle Scholar
  131. 131.
    Roffman JL, Petruzzi LJ, Tanner AS, et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry 2017 MAR 14.Google Scholar
  132. 132.
    Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336(8712):392-395.CrossRefPubMedGoogle Scholar
  133. 133.
    Morrison LD, Smith DD, Kish SJ. Brain S-Adenosylmethionine levels are severely decreased in alzheimer's disease. J Neurochem. 1996;67(3):1328-1331.CrossRefPubMedGoogle Scholar
  134. 134.
    Kennedy BP, Bottiglieri T, Arning E, et al. Elevated s-adenosylhomocysteine in alzheimer brain: influence on methyltransferases and cognitive function. J Neural Transm (VIENNA). 2004;111(4):547-567.CrossRefPubMedGoogle Scholar
  135. 135.
    Bradley-Whitman MA, Lovell MA. Epigenetic changes in the progression of alzheimer's disease. Mech Ageing Dev. 2013;134(10):486-495.CrossRefPubMedGoogle Scholar
  136. 136.
    Coppieters N, Dieriks BV, Lill C, et al. Global changes in dna methylation and hydroxymethylation in alzheimer's disease human brain. Neurobiol Aging. 2014;35(6):1334-1344.CrossRefPubMedGoogle Scholar
  137. 137.
    Chaney MO, Baudry J, Esh C, et al. A beta, aging, and alzheimer's disease: a tale, models, and hypotheses. Neurol Res. 2003;25(6):581-589.CrossRefPubMedGoogle Scholar
  138. 138.
    Iwata A, Nagata K, Hatsuta H, et al. Altered CPG Methylation in Sporadic alzheimer's disease is associated with APP and MAPT Dysregulation. Hum Mol Genet. 2014;23(3):648-656.CrossRefPubMedGoogle Scholar
  139. 139.
    Tohgi H, Utsugisawa K, Nagane Y, et al. Reduction with age in methylcytosine in the promoter region –224 approximately –101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res Mol Brain Res. 1999;70(2):288-292.CrossRefPubMedGoogle Scholar
  140. 140.
    Scarpa S, Fuso A, D'Anselmi F, et al. Presenilin 1 gene silencing by s-adenosylmethionine: a treatment for alzheimer disease? Febs Lett. 2003;541(1-3):145-148.CrossRefPubMedGoogle Scholar
  141. 141.
    Fuso A, Cavallaro RA, Zampelli A, et al. Gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells. J Alzheimers Dis. 2007;11(3):275-290.CrossRefPubMedGoogle Scholar
  142. 142.
    Fuso A, Nicolia V, Cavallaro RA, et al. B-Vitamin deprivation induces hyperhomocysteinemia and brain s-adenosylhomocysteine, depletes brain s-adenosylmethionine, and enhances PS1 and bace expression and amyloid-beta deposition in mice. Mol Cell Neurosci. 2008;37(4):731-746.CrossRefPubMedGoogle Scholar
  143. 143.
    Fuso A, Nicolia V, Pasqualato A, et al. Changes in presenilin 1 Gene methylation pattern in diet-induced b vitamin deficiency. Neurobiol Aging. 2011;32(2):187-199.CrossRefPubMedGoogle Scholar
  144. 144.
    Hodgson N, Trivedi M, Muratore C, et al. Soluble oligomers of amyloid-beta cause changes in redox state, DNA methylation, and gene transcription by inhibiting EAAT3 mediated cysteine uptake. J Alzheimers Dis. 2013;36(1):197-209.PubMedGoogle Scholar
  145. 145.
    Liu H, Li W, Zhao S, et al. Folic acid attenuates the effects of amyloid beta oligomers on dna methylation in neuronal cells. Eur J Nutr. 2016;55(5):1849-1862.CrossRefPubMedGoogle Scholar
  146. 146.
    Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset alzheimer's disease. Plos One. 2008;3(7):E2698.PubMedCentralCrossRefPubMedGoogle Scholar
  147. 147.
    Mastroeni D, Grover A, Delvaux E, et al. Epigenetic changes in alzheimer's disease: decrements in dna methylation. Neurobiol Aging. 2010;31(12):2025-2037.CrossRefPubMedGoogle Scholar
  148. 148.
    Nicolia V, Fuso A, Cavallaro RA, et al. B Vitamin deficiency promotes tau phosphorylation through regulation of GSK3BETA and PP2A. J Alzheimers Dis. 2010;19(3):895-907.CrossRefPubMedGoogle Scholar
  149. 149.
    Chen H, Dzitoyeva S, Manev H. Effect of aging on 5-hydroxymethylcytosine in the mouse hippocampus. Restor Neurol Neurosci. 2012;30(3):237-245.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Phipps AJ, Vickers JC, Taberlay PC, et al. Neurofilament-Labeled Pyramidal neurons and astrocytes are deficient in dna methylation marks in alzheimer's disease. Neurobiol Aging. 2016;45:30-42.CrossRefPubMedGoogle Scholar
  151. 151.
    Padurariu M, Ciobica A, Mavroudis I, et al. Hippocampal Neuronal Loss in the CA1 and CA3 areas of alzheimer's disease patients. Psychiatr Danub. 2012;24(2):152-158.PubMedGoogle Scholar
  152. 152.
    Jin SG, Wu X, Li AX, et al. Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res. 2011;39(12):5015-5024.PubMedCentralCrossRefPubMedGoogle Scholar
  153. 153.
    Bernstein AI, Lin Y, Street RC, et al. 5-Hydroxymethylation-Associated epigenetic modifiers of alzheimer's disease modulate tau-induced neurotoxicity. Hum Mol Genet. 2016;25(12):2437-2450.PubMedCentralPubMedGoogle Scholar
  154. 154.
    Ellison EM, Abner EL, Lovell MA. Multiregional Analysis of global 5-methylcytosine and 5-hydroxymethylcytosine throughout the progression of alzheimer's disease. J Neurochem. 2017;140(3):383-394.PubMedCentralCrossRefPubMedGoogle Scholar
  155. 155.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074-1080.CrossRefPubMedGoogle Scholar
  156. 156.
    Fiszbein A, Kornblihtt AR. Histone methylation, alternative splicing and neuronal differentiation. Neurogenesis (AUSTIN). 2016;3(1):E1204844.PubMedCentralCrossRefPubMedGoogle Scholar
  157. 157.
    Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005;6(11):838-849.CrossRefPubMedGoogle Scholar
  158. 158.
    Morse SJ, Butler AA, Davis RL, et al. Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits. Biology (BASEL). 2015;4(2):298-313.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Patel A, Dharmarajan V, Vought VE, et al. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (mll1) core complex. J Biol Chem. 2009;284(36):24242-24256.PubMedCentralCrossRefPubMedGoogle Scholar
  160. 160.
    Wu H, Min J, Lunin VV, et al. Structural biology of human H3K9 Methyltransferases. Plos One. 2010;5(1):E8570.PubMedCentralCrossRefPubMedGoogle Scholar
  161. 161.
    Horiuchi KY, Eason MM, Ferry JJ, et al. Assay development for histone methyltransferases. Assay Drug Dev Technol. 2013;11(4):227-236.PubMedCentralCrossRefPubMedGoogle Scholar
  162. 162.
    Sadhu MJ, Guan Q, Li F, et al. Nutritional control of epigenetic processes in yeast and human cells. Genetics. 2013;195(3):831-844.PubMedCentralCrossRefPubMedGoogle Scholar
  163. 163.
    Mentch SJ, Mehrmohamadi M, Huang L, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 2015;22(5):861-873.PubMedCentralCrossRefPubMedGoogle Scholar
  164. 164.
    Liu M, Barnes VL, Pile LA. Disruption of methionine metabolism in drosophila melanogaster impacts histone methylation and results in loss of viability. G3 (BETHESDA). 2015;6(1):121-132.CrossRefGoogle Scholar
  165. 165.
    Sperber H, Mathieu J, Wang Y, et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol. 2015;17(12):1523-1535.PubMedCentralCrossRefPubMedGoogle Scholar
  166. 166.
    Ara AI, Xia M, Ramani K, et al. S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. Hepatology. 2008;47(5):1655-1666.PubMedCentralCrossRefPubMedGoogle Scholar
  167. 167.
    Van Kanegan MJ, Adams DG, Wadzinski BE, et al. Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and AKT. J Biol Chem. 2005;280(43):36029-36036.CrossRefPubMedGoogle Scholar
  168. 168.
    Stanevich V, Jiang L, Satyshur KA, et al. The structural basis for tight control of PP2A Methylation and function by LCMT-1. Mol Cell. 2011;41(3):331-342.PubMedCentralCrossRefPubMedGoogle Scholar
  169. 169.
    Xing Y, Li Z, Chen Y, et al. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 2008;133(1):154-163.CrossRefPubMedGoogle Scholar
  170. 170.
    De Baere I, Derua R, Janssens V, et al. Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue. Biochemistry. 1999;38(50):16539-16547.CrossRefPubMedGoogle Scholar
  171. 171.
    Sontag E, Hladik C, Montgomery L, et al. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to alzheimer disease pathogenesis. J Neuropathol Exp Neurol. 2004;63(10):1080-1091.CrossRefPubMedGoogle Scholar
  172. 172.
    Nicholls RE, Sontag JM, Zhang H, et al. PP2A Methylation controls sensitivity and resistance to Beta-Amyloid-Induced Cognitive and electrophysiological impairments. Proc Natl Acad Sci U S A. 2016;113(12):3347-3352.PubMedCentralCrossRefPubMedGoogle Scholar
  173. 173.
    Sontag E, Nunbhakdi-Craig V, Sontag JM, et al. Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci. 2007;27(11):2751-2759.CrossRefPubMedGoogle Scholar
  174. 174.
    Sontag JM, Nunbhakdi-Craig V, Montgomery L, et al. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(ALPHA) Subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008;28(45):11477-11487.PubMedCentralCrossRefPubMedGoogle Scholar
  175. 175.
    Yoon SY, Choi HI, Choi JE, et al. Methotrexate decreases PP2A Methylation and increases tau phosphorylation in neuron. Biochem Biophys Res Commun. 2007;363(3):811-816.CrossRefPubMedGoogle Scholar
  176. 176.
    Brummelte S, Mc Glanaghy E, Bonnin A, et al. Developmental changes in serotonin signaling: implications for early brain function, behavior and adaptation. Neuroscience. 2017;342:212-231.CrossRefPubMedGoogle Scholar
  177. 177.
    Losada ME, Rubio MC. Acute effects of S-Adenosyl-L-Methionine on catecholaminergic central function. Eur J Pharmacol. 1989;163(2-3):353-356.CrossRefPubMedGoogle Scholar
  178. 178.
    Mischoulon D, Fava M. Role of S-Adenosyl-L-Methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(5):1158S-1161S.CrossRefPubMedGoogle Scholar
  179. 179.
    Otero-Losada ME, Rubio MC. Acute changes in 5-HT Metabolism after S-Adenosyl-L-Methionine administration. Gen Pharmacol. 1989;20(4):403-406.CrossRefPubMedGoogle Scholar
  180. 180.
    Moat SJ, Clarke ZL, Madhavan AK, et al. Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. Eur J Pharmacol. 2006;530(3):250-258.CrossRefPubMedGoogle Scholar
  181. 181.
    Sumi-Ichinose C, Urano F, Kuroda R, et al. Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. a study from 6-Pyruvoyltetrahydropterin synthase knockout mice. J Biol Chem. 2001;276(44):41150-60.CrossRefPubMedGoogle Scholar
  182. 182.
    Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232.PubMedCentralCrossRefPubMedGoogle Scholar
  183. 183.
    Tsao D, Diatchenko L, Dokholyan NV. Structural mechanism of S-Adenosyl methionine binding to catechol O-methyltransferase. Plos One. 2011;6(8):E24287.PubMedCentralCrossRefPubMedGoogle Scholar
  184. 184.
    Bellido I, Gomez-Luque A, Plaza A, et al. S-adenosyl-L-Methionine prevents 5-HT(1A) receptors up-regulation induced by acute imipramine in the frontal cortex of the rat. Neurosci Lett. 2002;321(1-2):110-114.CrossRefPubMedGoogle Scholar
  185. 185.
    Tsao D, Wieskopf JS, Rashid N, et al. Serotonin-induced hypersensitivity via inhibition of catechol O-Methyltransferase Activity. Mol Pain. 2012;8:25.PubMedCentralCrossRefPubMedGoogle Scholar
  186. 186.
    Obeid R, Herrmann W. Homocysteine and Lipids: S-Adenosyl Methionine As A Key Intermediate. FEBS LETT. 2009;583(8):1215-1225.CrossRefPubMedGoogle Scholar
  187. 187.
    Hao X, Huang Y, Qiu M, et al. Immunoassay of S-adenosylmethionine and S-adenosylhomocysteine: the methylation index as a biomarker for disease and health status. BMC Res Notes 2016; 9:498.PubMedCentralCrossRefPubMedGoogle Scholar
  188. 188.
    Reul JM. Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Front Psychiatry. 2014;5:5.PubMedCentralCrossRefPubMedGoogle Scholar
  189. 189.
    Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25(47):11045-11054.CrossRefPubMedGoogle Scholar
  190. 190.
    Mischoulon D, Alpert JE, Arning E, et al. Bioavailability of S-Adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. J Clin Psychiatry. 2012;73(6):843-848.PubMedCentralCrossRefPubMedGoogle Scholar
  191. 191.
    Galizia I, Oldani L, Macritchie K, et al. S-adenosyl methionine (SAME) for depression in adults. Cochrane Database Syst Rev. 2016;10:CD011286.PubMedGoogle Scholar
  192. 192.
    De Berardis D, Marini S, Serroni N, et al. S-adenosyl-L-methionine augmentation in patients with stage ii treatment-resistant major depressive disorder: an open label, fixed dose, single-blind study. Scientific World Journal. 2013;2013:204649.PubMedCentralCrossRefPubMedGoogle Scholar
  193. 193.
    Strous RD, Ritsner MS, Adler S, et al. Improvement of aggressive behavior and quality of life impairment following s-adenosyl-methionine (sam-e) augmentation in schizophrenia. Eur Neuropsychopharmacol. 2009;19(1):14-22.CrossRefPubMedGoogle Scholar
  194. 194.
    Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid s-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet. 1991;338(8782-8783):1550-1554.CrossRefPubMedGoogle Scholar
  195. 195.
    Loehrer FM, Schwab R, Angst CP, et al. Influence of oral S-adenosylmethionine on Plasma 5-Methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997;282(2):845-850.PubMedGoogle Scholar
  196. 196.
    Lee S, Lemere CA, Frost JL, et al. Dietary supplementation with s-adenosyl methionine delayed amyloid-beta and tau pathology in 3xtg-ad mice. J Alzheimers Dis. 2012;28(2):423-431.PubMedGoogle Scholar
  197. 197.
    Fuso A, Nicolia V, Ricceri L, et al. S-adenosylmethionine reduces the progress of the alzheimer-like features induced by b-vitamin deficiency in mice. Neurobiol Aging. 2012;33(7):1482 E1-16.CrossRefGoogle Scholar
  198. 198.
    Persichilli S, Gervasoni J, Di Napoli A, et al. Plasma thiols levels in alzheimer's disease mice under diet-induced hyperhomocysteinemia: effect of s-adenosylmethionine and superoxide-dismutase supplementation. J Alzheimers Dis. 2015;44(4):1323-1331.PubMedGoogle Scholar
  199. 199.
    Do Carmo S, Hanzel CE, Jacobs ML, et al. Rescue of early bace-1 and Global dna demethylation by S-Adenosylmethionine reduces amyloid pathology and improves cognition in an alzheimer's model. Sci Rep. 2016;6:34051.PubMedCentralCrossRefPubMedGoogle Scholar
  200. 200.
    Bustamante AC, Aiello AE, Galea S, et al. Glucocorticoid receptor DNA Methylation, Childhood Maltreatment And Major Depression. J Affect Disord. 2016;206:181-188.PubMedCentralCrossRefPubMedGoogle Scholar
  201. 201.
    Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75(4):324-331.CrossRefPubMedGoogle Scholar
  202. 202.
    Stefano P, Concetta C, Luigi D, et al. Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in alzheimer's disease. J Neurol Sci. 2016;370:162-166.CrossRefGoogle Scholar
  203. 203.
    Song Z, Uriarte S, Sahoo R, et al. S-Adenosylmethionine (SAME) modulates interleukin-10 and interleukin-6, but not tnf, production via the adenosine (A2) receptor. Biochim Biophys Acta. 2005;1743(3):205-213.CrossRefPubMedGoogle Scholar
  204. 204.
    Gobejishvili L, Avila DV, Barker DF, et al. S-Adenosylmethionine decreases lipopolysaccharide-induced phosphodiesterase 4B2 and attenuates tumor necrosis factor expression via camp/protein kinase a pathway. J Pharmacol Exp Ther. 2011;337(2):433-443.PubMedCentralCrossRefPubMedGoogle Scholar
  205. 205.
    Pfalzer AC, Choi SW, Tammen SA, et al. S-Adenosylmethionine mediates inhibition of inflammatory response and changes in dna methylation in human macrophages. Physiol Genomics. 2014;46(17):617-623.CrossRefPubMedGoogle Scholar
  206. 206.
    Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 british association for psychopharmacology guidelines. J Psychopharmacol. 2015;29(5):459-525.CrossRefPubMedGoogle Scholar
  207. 207.
    Remington R, Bechtel C, Larsen D, et al. A phase ii randomized clinical trial of a nutritional formulation for cognition and mood in alzheimer's disease. J Alzheimers Dis. 2015;45(2):395-405.PubMedGoogle Scholar
  208. 208.
    Mischoulon D, Price LH, Carpenter LL, et al. A double-blind, randomized, placebo-controlled clinical trial of S-Adenosyl-L-methionine (SAME) Versus Escitalopram In Major Depressive Disorder. J Clin Psychiatry. 2014;75(4):370-376.PubMedCentralCrossRefPubMedGoogle Scholar
  209. 209.
    Cho HH, Cahill CM, Vanderburg CR, Scherzer CR, Wang B, Huang X, Rogers JT. Selective Translational Control of the Alzheimer’s Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1. J. Biol. Chem. (cover issue), 2010;(285)31217-32.Google Scholar
  210. 210.
    Lippi G, Mattiuzzi C, Meschi T, et al. Homocysteine and migraine. a narrative review. Clin Chim Acta. 2014;433:5-11.CrossRefPubMedGoogle Scholar
  211. 211.
    Hao, X., et al., Novel immunoassays to detect methionine adenosyltransferase activity and quantify S-adenosylmethionine. FEBS Lett, 2017. 591(8): p. 1114-1125.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  • Jin Gao
    • 1
    • 2
    • 3
  • Catherine M. Cahill
    • 2
  • Xudong Huang
    • 2
  • Joshua L. Roffman
    • 1
  • Stefania Lamon-Fava
    • 4
  • Maurizio Fava
    • 1
  • David Mischoulon
    • 1
  • Jack T. Rogers
    • 2
  1. 1.Department of PsychiatryMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Neurochemistry Laboratory, Department of PsychiatryMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Department of Clinical PsychologyQilu Hospital of Shandong UniversityQingdaoChina
  4. 4.Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts UniversityBostonUSA

Personalised recommendations