, Volume 10, Issue 4, pp 722–733 | Cite as

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms



Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS.


Chromatin modification DNA methyltransferase 5-methylcytosine mitochondria motor neuron RG108. 

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  1. 1.
    Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Eng J Med 2001;344:1688-1700.Google Scholar
  2. 2.
    Zoccolella S, Santamato A, Lamberti P. Current and emerging treatments for amyotrophic lateral sclerosis. Neuropsychiatr Dis Treat 2009;5:577-595.PubMedGoogle Scholar
  3. 3.
    Eisen A. Amyotrophic lateral sclerosis: a 40-year personal perspective. J Clin Neurosci 2009;16:505-512.PubMedGoogle Scholar
  4. 4.
    Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve 2002;26:438-458.PubMedGoogle Scholar
  5. 5.
    Martin LJ. Mitochondrial and cell death mechanisms in neurodegenerative diseases. Pharmaceuticals 2010;3:839-915.PubMedGoogle Scholar
  6. 6.
    Martin LJ. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs 2010;13:568-580.PubMedGoogle Scholar
  7. 7.
    Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62.PubMedGoogle Scholar
  8. 8.
    Morris HR, Waite AJ, Williams NM, Neal JW, Blake DJ. Recent advances in the genetics of the ALS-FTLD complex. Curr Neurol Neurosci 2012;12:243-250.Google Scholar
  9. 9.
    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;72:257-268.PubMedGoogle Scholar
  10. 10.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007;128:683-692.PubMedGoogle Scholar
  11. 11.
    Al-Chalabi A, Fang F, Hanby MF, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 2010;81:1324-1326.PubMedGoogle Scholar
  12. 12.
    Fraga M, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Nat Acad Sci 2005;102:10604-10609.PubMedGoogle Scholar
  13. 13.
    Schymick JC, Talbot K, Traynor BJ. Genetics of sporadic amyotrophic lateral sclerosis Hum Mol Gen 2007;16:R233-R242.PubMedGoogle Scholar
  14. 14.
    Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 2008;85:94-134.PubMedGoogle Scholar
  15. 15.
    Redler RL, Dokholyan NV. The complex molecular biology of amyotrophic lateral sclerosis. Prog Mol Biol Trans Sci 2012;107:215-262.Google Scholar
  16. 16.
    Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006;52:39-59.PubMedGoogle Scholar
  17. 17.
    Qureshi IA, Mehler ME. Advances in epigenetics and epigenomics for neurodegenerative diseases. Curr Neurol Neurosci Rep 2011;11:464-473.PubMedGoogle Scholar
  18. 18.
    Wolffe AP, Matzke MA. Epigenetics: Regulation through repression. Science 1999;286:481-486.PubMedGoogle Scholar
  19. 19.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 2003;33(Suppl.):245-254.PubMedGoogle Scholar
  20. 20.
    Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012;13:484-492.PubMedGoogle Scholar
  21. 21.
    Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999;98:285-294.Google Scholar
  22. 22.
    Levenson JM, Roth TL, Lubin FD, et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 2006;281:15763-15773.PubMedGoogle Scholar
  23. 23.
    Curradi M, Izzo A, Badaracco G, Landsberger N. Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol 2002;22:3157-3173.PubMedGoogle Scholar
  24. 24.
    Yang X, Yan, L, Davidson N. DNA methylation in breast cancer. Endocr Relat Cancer 2001;8:115-127.PubMedGoogle Scholar
  25. 25.
    Luczak MW, Jagodzinski PP. The role of DNA methylation in cancer development. Folia Histochem Cytobiol 2006;44:143-154.PubMedGoogle Scholar
  26. 26.
    Cheng X. Structure and function of DNA methyltransferases. Ann Rev Biophys Biomol Struct 1995;24:293-318.Google Scholar
  27. 27.
    Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase I: expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 1999;274:33002-33010.PubMedGoogle Scholar
  28. 28.
    Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet 2000;9:2395-2402.PubMedGoogle Scholar
  29. 29.
    Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmcol Toxicol 2009;49:243-263.Google Scholar
  30. 30.
    Mazin AL. Suicidal function of DNA methylation in age-related genome disintegration. Ageing Res Rev 2009;8:314-327.PubMedGoogle Scholar
  31. 31.
    Brenner C, Fuks F. DNA methyltransferases: Facts, clues, mysteries. Curr Top Microbiol Immunol 2006;301:45-66.PubMedGoogle Scholar
  32. 32.
    Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6-21.PubMedGoogle Scholar
  33. 33.
    Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J Mol Biol 1987;196:261-282.PubMedGoogle Scholar
  34. 34.
    Fatemi M, Pao M, Jeong S, et al. Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Res 2005;33:e176.PubMedGoogle Scholar
  35. 35.
    Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science 2001;293:1068-1070.PubMedGoogle Scholar
  36. 36.
    Kimura H, Shiota K. Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1. J Biol Chem 2003;278:4806-4812.PubMedGoogle Scholar
  37. 37.
    Varley KE, Gertz J, Bowling KM, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res 2013;23:555-567.PubMedGoogle Scholar
  38. 38.
    Barres R, Osler ME, Yan J, et al. Non-CpG methylation of the PGP-1α promoter through DNMT3B controls mitochondrial density. Cell Metab 2009;10:189-198.PubMedGoogle Scholar
  39. 39.
    Ziller MJ, Muller F, Liao J, et al. Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet 2001;7:e1002389.Google Scholar
  40. 40.
    Maunakea AK, Nagarajan RP, Bilenky M, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010;466:253-260.PubMedGoogle Scholar
  41. 41.
    Wu H, Coskun V, Tao J, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 2010;329:444-448.PubMedGoogle Scholar
  42. 42.
    Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons in the brain. Science 2009;324:929-930.PubMedGoogle Scholar
  43. 43.
    Tahiliani M, Koh, KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylytosine in mammalian DNA by MLL partner TET1. Science 2009;324:930-935.PubMedGoogle Scholar
  44. 44.
    Jin S-G, Wu X, Li A, Pfeifer GP. Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nuc Acids Res 2011;39:5015-5024.Google Scholar
  45. 45.
    Wu SC, Zhang Y. Active DNA methylation: many roads lead to Rome. Nat Rev Mol Cell Biol 2010;11:607-620.PubMedGoogle Scholar
  46. 46.
    Globisch D, Münzel M, Müller M, et al. Tissue distribution of 5-hydroxymethlycytosine and search for active demethylation intermediates. PLoS One 2010;5:e15367.PubMedGoogle Scholar
  47. 47.
    Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001;20:31-39.Google Scholar
  48. 48.
    Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H. Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci USA 2005;102:8905-8909.PubMedGoogle Scholar
  49. 49.
    Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to from a complex at replication foci. Nature Genet 2000;24:269-277.Google Scholar
  50. 50.
    Espada J. Non-catalytic functions of DNMT1. Epigenetics 2012;7:115-118.PubMedGoogle Scholar
  51. 51.
    Schaefer M, Lyko F. Solving the Dnmt2 enigma. Chromosoma 2010;119:35-40.PubMedGoogle Scholar
  52. 52.
    Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-257.PubMedGoogle Scholar
  53. 53.
    Xie S, Wang Z, Okano M, Nogami M, Li Y, He WW, Okumura K, Li E. Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 1999; 236:87-95.PubMedGoogle Scholar
  54. 54.
    Kangaspeska S, Stride B, Métivier R, et al. Transient cyclical methylation of promoter DNA. Nature 2008;452:112-115.PubMedGoogle Scholar
  55. 55.
    Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 2007;449:248-251.PubMedGoogle Scholar
  56. 56.
    Hansen RS, Wijmenga C, Luo P, et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 1999;96:14412-14417.PubMedGoogle Scholar
  57. 57.
    Klein CJ, Botuyan M-V, Wu Y, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 2011;43:595-600.PubMedGoogle Scholar
  58. 58.
    Winkelman J, Lin L, Schormair B, et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 2012;21:2205-2210.Google Scholar
  59. 59.
    Easwaran HP, Schermelleh L, Leonhardt H, Cardoso MC. Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep 2004;5:1181-1186.PubMedGoogle Scholar
  60. 60.
    Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890-893.PubMedGoogle Scholar
  61. 61.
    Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 2001;69:915-926.Google Scholar
  62. 62.
    Endres M, Meisel A, Biniskiewicz D, et al. DNA methyltransferase contributes to delayed ischemia brain injury J Neurosci 2000;20:3175-3181.PubMedGoogle Scholar
  63. 63.
    Fan G, Beard C, Chen RZ, et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 2001;21:788-797.PubMedGoogle Scholar
  64. 64.
    Hutnick LK, Golshani P, Namihira M, et al. DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet 2009;18:2875-2888.PubMedGoogle Scholar
  65. 65.
    Nguyen S, Meletis K, Fu D, Jhaveri S, Jaenisch R. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened life span. Dev Dyn 2007;236:1663-1676.PubMedGoogle Scholar
  66. 66.
    Goto K, Numata M, Komura JI, et al. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 1994;56:39-44.PubMedGoogle Scholar
  67. 67.
    Brooks PJ, Marietta C, Goldman D. DNA mismatch repair and DNA methylation in adult brain neurons. J Neurosci 1996;16:939-945.PubMedGoogle Scholar
  68. 68.
    Inano K, Suetake I, Ueda T, et al. Maintenance-type DNA methyltransferases is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem 2000;128:315-321.PubMedGoogle Scholar
  69. 69.
    Feng J, Chang H, Li E, Fan G. Dynamic expression of de novo DNA methyltransferase DNMT3A and DNMT3B in the central nervous system. J Neurosci Res 2005;79:734-746.PubMedGoogle Scholar
  70. 70.
    Chestnut BA, Chang Q, Price A, Lesuisse C, Wong M, Martin LJ. Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci 2011;31:16619-16636.PubMedGoogle Scholar
  71. 71.
    Miller CA, Sweatt JD. Covalent modification of DNA regulates memory formation. Neuron 2007;53:857-869.PubMedGoogle Scholar
  72. 72.
    LaPlant Q, Vialou V, Covington HE 3rd, et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 2010;13:1137-1143.PubMedGoogle Scholar
  73. 73.
    Feng J, Zhou Y, Campbell SL, et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 2010;13:423-30.PubMedGoogle Scholar
  74. 74.
    Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A 2011;108:3630-3635.PubMedGoogle Scholar
  75. 75.
    Shmookler Reis RJ, Goldstein S. Mitochondrial DNA in mortal and immortal cells: Genome number, integrity, and methylation. J Biol Chem 258:1983;9078-9085.PubMedGoogle Scholar
  76. 76.
    Pollack Y, Kasir J, Shemer R, Metzger S, Szyf M. Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Res 1984;12:4811-4824.PubMedGoogle Scholar
  77. 77.
    Oates N, Pamphlett R. An epigenetic analysis of SOD1 and VEGF in ALS. Amyotroph Lateral Scler 2007;8:83-86.PubMedGoogle Scholar
  78. 78.
    Morahan JM, Yu B, Trent RJ, Pamphlett R. Are metallothionein genes silenced in ALS? Toxicol Lett 2007;168:83-87.PubMedGoogle Scholar
  79. 79.
    Yang Y, Gozen O, Vidensky S, Robinson MB, Rothstein JD. Epigenetic regulation of neuron-dependent induction of astroglial synaptic protein GLT1. Glia 2010;58:277-286.PubMedGoogle Scholar
  80. 80.
    Morahan JM, Yu B, Trent RJ, Pamphlett R. A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009;10:418-429.PubMedGoogle Scholar
  81. 81.
    Ladd-Acosta C, Pevsner J, Sabunciyan S, et al. DNA methylation signatures within the human brain. Am J Hum Genet 2007;81:1304-1315.PubMedGoogle Scholar
  82. 82.
    Nishioka M, Shimada T, Bundo M, et al. Neuronal cell-type specific DNA methylation patterns of the Cacna1 gene. Int J Devl Neurosci 2013;31:89-95Google Scholar
  83. 83.
    Figueroa-Romero C, Hur J, Bender DE, et al. Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis. PLoS ONE 2012;7:e52672.PubMedGoogle Scholar
  84. 84.
    Ginsberg SD, Hemby SE, Mufson EJ, Martin LJ. Cell and tissue microdissection in combination with genomic and proteomic applications. In: Zaborsky L, Wouterlood FG, Lanciego JL (eds) Neuroanatomical tract-tracing 3: molecules, neurons, and systems. Springer, Singapore, 2006, pp. 109-141.Google Scholar
  85. 85.
    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;72:245-256.PubMedGoogle Scholar
  86. 86.
    Xi Z, Zinman L, Moreno D, et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 2013;92:981-989.Google Scholar
  87. 87.
    Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001;29:166-173.PubMedGoogle Scholar
  88. 88.
    Yang Y, Hentati A, Deng HX et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001;29:160-165.PubMedGoogle Scholar
  89. 89.
    Labonte B, Suderman M, Maussion G, et al. Genome-wide epigenetic regulation by early-life trauma. Arch Gen Psychiatry 2012;69:722-731.PubMedGoogle Scholar
  90. 90.
    Martin LJ, Chen K, Liu Z. Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked to DNA damage and p53 activation. J Neurosci 2005; 25:6449-6459.PubMedGoogle Scholar
  91. 91.
    Martin LJ, Liu Z, Chen K, et al. Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol 2007;500:20-46.PubMedGoogle Scholar
  92. 92.
    Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 1999;58:459-471.PubMedGoogle Scholar
  93. 93.
    Martin LJ. p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis. Neurobiol Dis 2000;7:613-622.PubMedGoogle Scholar
  94. 94.
    Brueckner B, Garcia Boy R, Siedlecki P, et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 2005;65:6305-6311.PubMedGoogle Scholar
  95. 95.
    Lee BH, Yegnasubramanian S, Lin X, Nelson WG. Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem 2005;280:40749-40756.PubMedGoogle Scholar
  96. 96.
    Santourlidis S, Kimura F, Fischer J, Schulz WA. Suppression of clonogenicity by mammalian Dnmt1 mediated by the PCNA-binding domain. Biochem Cell Biol 2004;82:589-596.PubMedGoogle Scholar
  97. 97.
    Li HL, Ma AN. Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting surviving gene. Cancer Gene Therapy 2010;17:441-446.PubMedGoogle Scholar
  98. 98.
    Tolosa L, Mir M, Asensio VJ, et al. Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3-kinase. J Neurochem 2008;105:1080-1090.PubMedGoogle Scholar
  99. 99.
    Narayan A, Tuck-Muller C, Weissbecker K, et al. Hypersensitivity to radiation-induced non-apoptotic and apoptotic death in cell lines from patients with the ICF chromosome instability syndrome. Mut Res 2000;456:1-15.Google Scholar
  100. 100.
    Metivier R, Gallais R, Tiffoche C, et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008;452;45-50.PubMedGoogle Scholar
  101. 101.
    Nelson ED, Kavalali ET, Monteggia LM. Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 2008;28:395-406.PubMedGoogle Scholar
  102. 102.
    Chang Q, Martin LJ. Glycine receptor channels in spinal motoneurons are abnormal in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 2011;31:2815-2827.PubMedGoogle Scholar
  103. 103.
    Chang Q, Martin LJ. Glycinergic Innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a confocal quantitative analysis. Am J Path 2009;174:574-585.PubMedGoogle Scholar
  104. 104.
    Martin LJ, Chang Q. Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in ALS. Mol Neurobiol 2012;45:30-42.PubMedGoogle Scholar
  105. 105.
    McGown A, McDearmid JR, Panagiotaki N, et al. Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model. Ann Neurol 2001;73:246-258.Google Scholar
  106. 106.
    Turner MR, Kiernan MC. Does interneuronal dysfunction contribute to neurodegeneration in ALS? Amyotroph Lateral Scler 2012;13:245-250.PubMedGoogle Scholar
  107. 107.
    Matrisciano F, Tueting P, Dalal I, et al. Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology 2013;68:184-194.PubMedGoogle Scholar
  108. 108.
    McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 2002;26:459-470.PubMedGoogle Scholar
  109. 109.
    Harwood CA, McDermott CJ, Shaw PJ. Physical activity as an exogenous risk factor in motor neuron disease (MND): A review of the evidence. Amyotroph Lateral Scler 2009;10:191-204.PubMedGoogle Scholar
  110. 110.
    Huisman MHB, Seelen M, de Jong SW, et al. Lifetime physical activity and the risk of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013. doi:10.1136/jnnp-2012-304724.
  111. 111.
    Dupuis L, Pradat P-F, Ludolph AC, Loeffler J-P. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol 2011;10:75-82.PubMedGoogle Scholar
  112. 112.
    Ribel-Madsen R, Fraga MF, Jacobsen S, et al. Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS ONE 2012;7:e51302.PubMedGoogle Scholar
  113. 113.
    Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 2010;19:2284-2302.PubMedGoogle Scholar
  114. 114.
    Vielhaber S, Winkler K, Kirches E, et al. Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis. J Neurol Sci 1999;169:133-139.PubMedGoogle Scholar
  115. 115.
    Echaniz-Laguna A, Zoll J, Ponsot E, et al. Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: A temporal study in man. Exp Neurol 2006;198:25-30.PubMedGoogle Scholar
  116. 116.
    Pradat P-F, Barani A, Wanschitz J, et al. Abnormalities of satellite cells function in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011;12:264-271.PubMedGoogle Scholar
  117. 117.
    Donoghue MJ, Sanes JR. All muscles are not created equal. Trends Genet 1994;10:396-401.PubMedGoogle Scholar
  118. 118.
    Coffey AG, Hawley JA. The molecular bases of training adaptation. Sports Med 2007;37:737-763.PubMedGoogle Scholar
  119. 119.
    Barrès R, Yan J, Egan B, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 2012;15:405-411.PubMedGoogle Scholar
  120. 120.
    Nebbioso A, Carafa V, Benedetti R, Altucci L. Trials with ‘epigenetic’ drugs: an update. Mol Oncol 2012;6:657-682.PubMedGoogle Scholar
  121. 121.
    Baar K. Epigenetic control of skeletal muscle fiber type. Acta Physiol 2010;199:477-487.Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2013

Authors and Affiliations

  1. 1.Department of Pathology, Division of NeuropathologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Pathobiology Graduate ProgramJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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