Abstract
Neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease, are highly complex, due to their multifactorial origin, not only depending on genetic but also on environmental factors. Several genetic risk factors have already been associated with both the diseases, however, the precise way through which the environment contributes to neurodegeneration is still unclear.
Recently, epigenetic mechanisms, such as DNA methylation, chromatin remodeling or miRNAs, which may induce alterations in genes expression, have started to be implicated in both AD and PD. Epigenetic modulation is present since pre-natal stages and throughout lifetime, and depends on lifestyle conditions and environmental exposures, and consequently could represent the missing link between risk factors and the development of sporadic disorders. This chapter will discusses the role of epigenetics in AD and PD.
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References
Agirre X, Román-Gómez J, Vázquez I, Jiménez-Velasco A, Garate L, Montiel-Duarte C, Artieda P, Cordeu L, Lahortiga I, Calasanz MJ, Heiniger A, Torres A, Minna JD, Prósper F (2006) Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. Int J Cancer 118(8):1945–1953
Association A (2009) Alzheimer’s disease facts and figures. Alzheimers Dement 5:234–270
Bak M, Silahtaroglu A, Møller M, Christensen M, Rath MF, Skryabin B, Tommerup N, Kauppinen S (2008) MicroRNA expression in the adult mouse central nervous system. RNA 14(3):432–444
Bettens K, Sleegers K, Broeckhoven CV (2010) Current status on Alzheimer disease molecular genetics: from past, to present, to future. Hum Mol Genet 19(1):R4–R11
Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A, Nappi G (2001) Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease. Clin Chem 47(6):1102–1104
Boissonneault V, Plante I, Rivest S, Provost P (2009) MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. J Biol Chem 284(4):1971–1981
Bönsch D, Lenz B, Kornhuber J, Bleich S (2005) DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport 16(2):167–170
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurob Aging 24:197–211
Brami-Cherrier K, Valjent E, Hervé D, Darragh J, Corvol JC, Pages C, Arthur SJ, Girault JA, Caboche J (2005) Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J Neurosci 25(49):11444–11454
Burke RE, Dauer, Vonsattel JPG (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491
Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S (2010) CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 107(52):22687–22692
Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11(12):1116–1125
Darmopil S, Martín AB, De Diego IR, Ares S, Moratalla R (2009) Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation. Biol Psychiatry 66(6):603–613
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909
de Mena L, Coto E, Cardo LF, Díaz M, Blázquez M, Ribacoba R, Salvador C, Pastor P, Samaranch L, Moris G, Menéndez M, Corao A, Alvarez V (2010) Analysis of the Micro-RNA-133 and PITX3 genes in Parkinson’s disease. Am J Med Genet B 153B(6):1234–1239
Desplats P, Spencer B, Coffee E, Patel P, Michael S, Patrick C, Adame A, Rockenstein E, Masliah E (2011) Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem 286(11):9031–9037
Dolinoy DC, Jirtle RL (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49:4–8
Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem 80(1):101–110
Ertekin-Taner N (2007) Genetics of Alzheimer’s disease: a centennial review. Neurol Clin 25:611–667
Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG (2007) Levodopa-induced dyskinesias. Mov Disord 22(10):1379–1389
Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7:306–318
Finkelstein JD (2000) Pathways and regulation of homocysteine metabolism in mammals. Semin Thromb Hemost 26(3):219–225
Francis YI, Fà M, Ashrafa H, Zhanga H, Staniszewskia A, Latchmanb DS, Arancioa O (2009) Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer’s disease. J Alzheimers Dis 18:131–139
Frieling H, Gozner A, Römer KD, Lenz B, Bönsch D, Wilhelm J, Hillemacher T, de Zwaan M, Kornhuber J, Bleich S (2007) Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry 12(3):229–230
Fuso A, Seminara L, Cavallaro RA, D’Anselmi F, Scarpa S (2005) S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 28:195–204
Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D’Anselmi F, Coluccia P, Calamandrei G, Scarpa S (2008) 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 37(4):731–746
Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S (2011a) Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency. Neurobiol Aging 32(2):187–199
Fuso A, Nicolia V, Cavallaro RA, Scarpa S (2011b) DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer’s disease models. J Nutr Biochem 22(3):242–251
Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML (1995) Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. Stroke 26(7):1166–1170
Gillardon F, Mack M, Rist W, Schnack C, Lenter M, Hildebrandt T, Hengerer B (2008) MicroRNA and proteome expression profiling in early-symptomatic α-synuclein(A30P)-transgenic mice. Proteomics Clin Appl 2(5):697–705
Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C (2009) The genetics of Parkinson’s syndromes: a critical review. Curr Opin Genet Dev 19:254–265
Hébert SS, De Strooper B (2009) Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci 32(4):199–206
Jiang Q, Ren Y, Feng J (2008) Direct binding with histone deacetylase 6 mediates the reversible recruitment of parkin to the centrosome. J Neurosci 28(48):12993–13002
Jowaed A, Schmitt I, Kaut O, Wüllner U (2010) Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 30(18):6355–6359
Junn E, Lee K-W, Jeong BS, Chan TW, J-Y IM, Mouradian MM (2009) Repression of α-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci 106(31):13052–13057
Khandhar SM, Marks WJ (2007) Epidemiology of Parkinson’s disease. Dis Mon 53:200–205
Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35(4):870–880
Klein C, Schlossmacher MG (2007) Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology 69:2093–2104
Kontopoulos E, Parvin JD, Feany MB (2006) α-Synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15(20):3012–3023
Kovalchuk O (2008) Epigenetic research sheds new light on the nature of interactions between organisms and their environment. Environ Mol Mutagen 49:1–3
Lau LML, Breteler MB (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535
Lambert JC, Amouyel P (2007) Genetic heterogeneity of Alzheimer’s disease: complexity and advances. Psychoneuroendocrinology 32(1):S62–S70
Lukiw WJ, Zhan Y, Guo Cui J (2008) An NF-κB-sensitive Micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283:31315–31322
Maeda T, Guan JZ, Oyama J, Higuchi Y, Makino N (2009) Aging-associated alteration of subtelomeric methylation in Parkinson’s disease. J Gerontol A Biol Sci Med Sci 64(9):949–955
Marques SC, Oliveira CR, Outeiro TF, Pereira CM (2010) Alzheimer’s disease: the quest to understand complexity. J Alzheimers Dis 21(2):373–383
Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A (2010) CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS One 5(11):e15522
Minati L, Edginton T, Bruzzone MG, Giaccone G (2009) Current concepts in Alzheimer’s disease: a multidisciplinary review. Am J Alzheimers Dis Other Demen 24:95–121
Monti B, Gatta V, Piretti F, Raffaelli SS, Virgili M, Contestabile A (2010) Valproic acid is neuroprotective in the rotenone rat model of Parkinson’s disease: involvement of alpha-synuclein. Neurotox Res 17(2):130–141
Nicholas AP, Lubin FD, Hallett PJ, Vattem P, Ravenscroft P, Bezard E, Zhou S, Fox SH, Brotchie JM, Sweatt JD, Standaert DG (2008) Striatal histone modifications in models of levodopa-induced dyskinesia. J Neurochem 106(1):486–494
Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W (2009) Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem 55(10):1852–1860
Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837):516–519
Pacheco-Quinto J, de Turco EBR, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, Refolo I, Petancesk S, Pappolla MA (2006) Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid B peptide levels. Neurobiol Dis 22:651–656
Ray WJ, Ashall F, Goate AM (1998) Molecular pathogenesis of sporadic and familial forms of Alzheimer’s disease. Mol Med Today 4:151–157
Ricobaraza A, Cuadrado-Tejedor M, Pérez-Mediavilla A, Frechilla D, Del Río J, García-Osta A (2009) Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 34(7):1721–1732
Ricobaraza A, Cuadrado-Tejedor M, Marco S, Pérez-Otaño I, García-Osta A (2010) Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22(5):1040–1050
Rocchi A, Pellegrini S, Siciliano G, Murri L (2003) Review: causative and susceptibility genes for Alzheimer’s disease: a review. Brain Res Bull 61:1–24
Rouaux C, Jokic N, Mbebi C, Boutillier S, Loeffler JP, Boutillier AL (2003) Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J 22(24):6537–6549
Schipper HM, Maes OC, Chertkow HM, Wang E (2007) MicroRNA expression in Alzheimer blood mononuclear cells. Gene Regul Syst Biol 20(1):263–274
Silva PNO, Gigek CO, Leal MF, Bertolucci PHF, de Labio RW, Payão SLM, Smith MAC (2008) Promoter methylation analysis of SIRT3, SMARCA5, HTERT and CDH1 genes in aging and Alzheimer’s disease. J Alzheimers Dis 13:173–176
Song C, Kanthasamy A, Anantharam V, Sun F, Kanthasamy AG (2010) Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Mol Pharmacol 77(4):621–632
Sontag E, Hladik C, Montgomery L, Luangpirom A, Mudrak I, Ogris E, White CL 3rd (2004) Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol 63(10):1080–1091
Sontag E, Nunbhakdi-Craig V, Sontag JM, Diaz-Arrastia R, Ogris E, Dayal S, Lentz SR, Arning E, Bottiglieri T (2007) Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci 27:2751–2759
St George-Hyslop PH, Petit A (2004) Molecular biology and genetics of Alzheimer’s disease. Comptes Rendus Biologies 328:119–130
Stozicka Z, Zilka N, Novak M (2007) Review: risk and protective factors for sporadic Alzheimer’s disease. Acta Virol 51:205–222
Tanzi RE, Bertram L (2001) New frontiers in Alzheimer’s disease genetics. Neuron 32:181–184
Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Genda Y, Ukitsu M (1999) Reduction with age in methylcytosine in the promoter region −224–101 of the amyloid precursor protein gene in autopsy human cortex. Mol Brain Res 70:288–292
Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, Impey S (2005) A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci 102(45):16426–16431
Voutsinas GE, Stavrou EF, Karousos G, Dasoula A, Papachatzopoulou A, Syrrou M, Verkerk AJ, van der Spek P, Patrinos GP, Stöger R, Athanassiadou A (2010) Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Hum Mutat 31(6):685–691
Wang G, van der Walt JM, Mayhew G, Li Y, Zuchner S, Scott WK, Martin ER, Vance JM (2008a) Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of a-synuclein. Am J Hum Genet 82:283–289
Wang S-C, Oelze B, Schumacher A (2008b) Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS One 3:e2698
Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT (2008c) The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28(5):1213–1223
Wang X, Liu P, Zhu H, Xu Y, Ma C, Dai X, Huang L, Liu Y, Zhang L, Qin C (2009a) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80(4–5):268–273
Wang Y, Wang X, Liu L, Wang X (2009b) HDAC inhibitor trichostatin A-inhibited survival of dopaminergic neuronal cells. Neurosci Lett 467(3):212–216
Weintraub D, Comella CL, Horn S (2008) Parkinson’s disease- part 1: pathophysiology, symptoms, burden, diagnosis, and assessment. Am J Manag Care 14:S40–S48
Wood-Kaczmar A, Gandhi S, Wood NW (2006) Understanding the molecular causes of Parkinson’s disease. Trends Mol Med 12:521–528
World Health Organization (2002) Active ageing, a policy framework. Second United Nations World assembly on Aging, Madrid, Spain. www.who.int/hpr/ageing/ActiveAgingPolicyFrame.pdf
Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008a) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28:3–9
Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, Kinyamu H, Lu N, Gao X, Leng Y, Chuang DM, Zhang W, Lu RB, Hong JS (2008b) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11(8):1123–1134
Acknowledgements
TFO is supported by a Marie Curie International Reintegration Grant (Neurofold) and an EMBO Installation Grant. SM is supported by a fellowship from Fundação para Ciência e Tecnologia (SFRH/BD/33188/2007).
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Marques, S., Outeiro, T.F. (2013). Epigenetics in Parkinson’s and Alzheimer’s Diseases. In: Kundu, T. (eds) Epigenetics: Development and Disease. Subcellular Biochemistry, vol 61. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4525-4_22
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