Abstract
Adenosine A2A receptor (A2AR) is a G-protein-coupled receptor highly expressed in basal ganglia. Its expression levels are severely reduced in Huntington’s disease (HD), and several pharmacological therapies have shown its implication in this neurodegenerative disorder. The main goal of this study was to gain insight into the molecular mechanisms that regulate A2AR gene (ADORA2A) expression in HD. Based on previous data reported by our group, we measured the methylcytosine (5mC) and hydroxymethylcytosine (5hmC) content in the 5′UTR region of ADORA2A in the putamen of HD patients and in the striatum of R6/1 and R6/2 mice at late stages of the disease. In this genomic region, 5mC and 5hmC remained unchanged in both mice strains, although low striatal A2AR levels were associated with reduced 5mC levels in 30-week-old R6/1 mice and reduced 5hmC levels in 12-week-old R6/2 mice in exon m2. In order to analyze when this mechanism appears during the progression of the disease, a time course for A2AR protein levels was carried out in R6/1 mice striatum (8, 12, and 20 weeks of age). A2AR levels were reduced from 12 weeks of age onwards, and this downregulation was concomitant with reduced 5hmC levels in the 5′UTR region of ADORA2A. Interestingly, increased 5mC levels and reduced 5hmC were found in the 5′UTR region of ADORA2A in the putamen of HD patients with respect to age-matched controls. Therefore, an altered DNA methylation pattern in ADORA2A seems to play a role in the pathologically decreased A2AR expression levels found in HD.
Similar content being viewed by others
References
Assaife-Lopes, N., Sousa, V. C., Pereira, D. B., Ribeiro, J. A., Chao, M. V., & Sebastião, A. M. (2010). Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: Implications for neuromodulation. The Journal of Neuroscience, 30(25), 8468–8480.
Bañez-Coronel, M., Porta, S., Kagerbauer, B., Mateu-Huertas, E., Pantano, L., Ferrer, I., et al. (2012). A pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genetics, 8(2), e1002481.
Barrachina, M., & Ferrer, I. (2009). DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. Journal of Neuropathology and Experimental Neurology, 68(8), 880–891.
Bauer, A., Zilles, K., Matusch, A., Holzmann, C., Riess, O., & von Hörsten, S. (2005). Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington’s disease mutation. Journal of Neurochemistry, 94(3), 639–650.
Blum, D., Galas, M. C., Pintor, A., Brouillet, E., Ledent, C., Muller, C. E., et al. (2003). A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: Implications for the neuroprotective potential of A2A antagonists. The Journal of Neuroscience, 23(12), 5361–5369.
Brohede, J., Rinde, M., Winblad, B., & Graff, C. (2010). A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease. Journal of Neurogenetics, 24(4), 179–181.
Buira, S. P., Albasanz, J. L., Dentesano, G., Moreno, J., Martín, M., Ferrer, I., et al. (2010a). DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. Journal of Neurochemistry, 112(5), 1273–1285.
Buira, S. P., Dentesano, G., Albasanz, J. L., Moreno, J., Martín, M., Ferrer, I., et al. (2010b). DNA methylation and Yin Yang-1 repress adenosine A2A receptor levels in human brain. Journal of Neurochemistry, 115(1), 283–295.
Calon, F., Dridi, M., Hornykiewicz, O., Bédard, P. J., Rajput, A. H., & Di Paolo, T. (2004). Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain, 127(Pt 5), 1075–1084.
Cha, J. H., Frey, A. S., Alsdorf, S. A., Kerner, J. A., Kosinski, C. M., Mangiarini, L., et al. (1999). Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philosophical Transactions of the Royal Society of London. Series B, Biological Science, 354(1386), 981–989.
Chen-Plotkin, A. S., Sadri-Vakili, G., Yohrling, G. J., Braveman, M. W., Benn, C. L., Glajch, K. E., et al. (2006). Decreased association of the transcription factor Sp1 with genes downregulated in Huntington’s disease. Neurobiology of Disease, 22(2), 233–241.
Chiang, M. C., Chen, H. M., Lai, H. L., Chen, H. W., Chou, S. Y., Chen, C. M., et al. (2009). The A2A adenosine receptor rescues the urea cycle deficiency of Huntington’s disease by enhancing the activity of the ubiquitin-proteasome system. Human Molecular Genetics, 18(16), 2929–2942.
Chiang, M. C., Lee, Y. C., Huang, C. L., & Chern, Y. (2005). cAMP-response element-binding protein contributes to suppression of the A2A adenosine receptor promoter by mutant Huntingtin with expanded polyglutamine residues. The Journal of Biological Chemistry, 280(14), 14331–14340.
Choi, Y. J., Kim, S. I., Lee, J. W., Kwon, Y. S., Lee, H. J., Kim, S. S., et al. (2012). Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic cell death. Molecular and Cellular Neurosciences, 49(2), 127–137.
Cong, S. Y., Pepers, B. A., Evert, B. O., Rubinsztein, D. C., Roos, R. A., van Ommen, G. J., et al. (2005). Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Molecular and Cellular Neurosciences, 30(4), 560–571.
de Boni, L., Tierling, S., Roeber, S., Walter, J., Giese, A., & Kretzschmar, H. A. (2011). Next-generation sequencing reveals regional differences of the α-synuclein methylation state independent of Lewy body disease. NeuroMolecular Medicine, 13(4), 310–320.
Deckert, J., Brenner, M., Durany, N., Zöchling, R., Paulus, W., Ransmayr, G., et al. (2003). Up-regulation of striatal adenosine A(2A) receptors in schizophrenia. NeuroReport, 14(3), 313–316.
Dhaenens, C. M., Burnouf, S., Simonin, C., Van Brussel, E., Duhamel, A., Defebvre, L., et al. (2009). A genetic variation in the ADORA2A gene modifies age at onset in Huntington’s disease. Neurobiology of Disease, 35(3), 474–476.
Feng, J., Zhou, Y., Campbell, S. L., Le, T., Li, E., Sweatt, J. D., et al. (2010). Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nature Neuroscience, 13(4), 423–430.
Ferrer, I., Goutan, E., Marín, C., Rey, M. J., & Ribalta, T. (2000). Brain-derived neurotrophic factor in Huntington disease. Brain Research, 866(1–2), 257–261.
Ferrer, I., Martinez, A., Boluda, S., Parchi, P., & Barrachina, M. (2008). Brain banks: Benefits, limitations and cautions concerning the use of post-mortem brain tissue for molecular studies. Cell and Tissue Banking, 9(3), 181–194.
Fredholm, B. B., Ijzerman, A. P., Jacobson, K. A., Klotz, K. N., & Linden, J. (2001). International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological Reviews, 53(4), 527–552.
Gianfriddo, M., Melani, A., Turchi, D., Giovannini, M. G., & Pedata, F. (2004). Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow. Neurobiology of Disease, 17(1), 77–88.
Ginés, S., Bosch, M., Marco, S., Gavaldà, N., Díaz-Hernández, M., Lucas, J. J., et al. (2006). Reduced expression of the TrkB receptor in Huntington’s disease mouse models and in human brain. The European Journal of Neuroscience, 23(3), 649–658.
Giralt, A., Saavedra, A., Carreton, O., Xifro, X., Alberch, J., & Perez-Navarro, E. (2011). Increased PKA signaling disrupts recognition memory and spatial memory: Role in Huntington’s disease. Human Molecular Genetics, 20(21), 4232–4247.
Glass, M., Dragunow, M., & Faull, R. L. (2000). The pattern of neurodegeneration in Huntington’s disease: A comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience, 97(3), 505–519.
Globisch, D., Münzel, M., Müller, M., Michalakis, S., Wagner, M., Koch, S., et al. (2010). Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS ONE, 5(12), e15367.
Guo, J. U., Ma, D. K., Mo, H., Ball, M. P., Jang, M. H., Bonaguidi, M. A., et al. (2011a). Neuronal activity modifies the DNA methylation landscape in the adult brain. Nature Neuroscience, 14(10), 1345–1351.
Guo, J. U., Su, Y., Zhong, C., Ming, G. L., & Song, H. (2011b). Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell, 145(3), 423–434.
Hodges, A., Strand, A. D., Aragaki, A. K., Kuhn, A., Sengstag, T., Hughes, G., et al. (2006). Regional and cellular gene expression changes in human Huntington’s disease brain. Human Molecular Genetics, 15(6), 965–977.
Huang, N. K., Lin, J. H., Lin, J. T., Lin, C. I., Liu, E. M., Lin, C. J., et al. (2011). A new drug design targeting the adenosinergic system for Huntington’s disease. PLoS ONE, 6(6), e20934.
Huang, H. S., Matevossian, A., Jiang, Y., & Akbarian, S. (2006). Chromatin immunoprecipitation in postmortem brain. Journal of Neuroscience Methods, 156(1–2), 284–292.
Ishiwata, K., Ogi, N., Hayakawa, N., Oda, K., Nagaoka, T., Toyama, H., et al. (2002). Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: comparison with the dopamine receptor imaging. Annals of Nuclear Medicine, 16(7), 467–475.
Jin, S. G., Kadam, S., & Pfeifer, G. P. (2010). Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Research, 38(11), e125.
Jin, S. G., Wu, X., Li, A. X., & Pfeifer, G. P. (2011). Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Research, 39(12), 5015–5024.
Jones, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Reviews Genetics, 13(7), 484–492.
Jowaed, A., Schmitt, I., Kaut, O., & Wüllner, U. (2010). Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. The Journal of Neuroscience, 30(18), 6355–6359.
Khare, T., Pai, S., Koncevicius, K., Pal, M., Kriukiene, E., Liutkeviciute, Z., et al. (2012). 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nature Structural & Molecular Biology, 19(10), 1037–1043.
Kriaucionis, S., & Heintz, N. (2009). The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science, 324(5929), 929–930.
Kuhn, A., Goldstein, D. R., Hodges, A., Strand, A. D., Sengstag, T., Kooperberg, C., et al. (2007). Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Human Molecular Genetics, 16(15), 1845–1861.
Li, S. H., Cheng, A. L., Zhou, H., Lam, S., Rao, M., Li, H., et al. (2002). Interaction of Huntington disease protein with transcriptional activator Sp1. Molecular and Cellular Biology, 22(5), 1277–1287.
London, E. D., Yamamura, H. I., Bird, E. D., & Coyle, J. T. (1981). Decreased receptor-binding sites for kainic acid in brains of patients with Huntington’s disease. Biological Psychiatry, 16(2), 155–162.
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., et al. (1996). Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87(3), 493–506.
Martinez-Mir, M. I., Probst, A., & Palacios, J. M. (1991). Adenosine A2 receptors: Selective localization in the human basal ganglia and alterations with disease. Neuroscience, 42(3), 697–706.
Matsumoto, L., Takuma, H., Tamaoka, A., Kurisaki, H., Date, H., Tsuji, S., et al. (2010). CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS ONE, 5(11), e15522.
Mievis, S., Blum, D., & Ledent, C. (2011). A2A receptor knockout worsens survival and motor behaviour in a transgenic mouse model of Huntington’s disease. Neurobiology of Disease, 41(2), 570–576.
Miller, C. A., Gavin, C. F., White, J. A., Parrish, R. R., Honasoge, A., Yancey, C. R., et al. (2010). Cortical DNA methylation maintains remote memory. Nature Neuroscience, 13(6), 664–666.
Miller, C. A., & Sweatt, J. D. (2007). Covalent modification of DNA regulates memory formation. Neuron, 53(6), 857–869.
Mishina, M., Ishiwata, K., Naganawa, M., Kimura, Y., Kitamura, S., Suzuki, M., et al. (2011). Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson’s disease patients. PLoS ONE, 6(2), e17338.
Münzel, M., Globisch, D., Brückl, T., Wagner, M., Welzmiller, V., Michalakis, S., et al. (2010). Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angewandte Chemie (International ed. in English), 49(31), 5375–5377.
Münzel, M., Globisch, D., & Carell, T. (2011). 5-Hydroxymethylcytosine, the sixth base of the genome. Angewandte Chemie (International ed. in English), 50(29), 6460–6468.
Nucifora, F. C, Jr, Sasaki, M., Peters, M. F., Huang, H., Cooper, J. K., Yamada, M., et al. (2001). Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science, 291(5512), 2423–2428.
Orrú, M., Zanoveli, J. M., Quiroz, C., Nguyen, H. P., Guitart, X., & Ferré, S. (2011). Functional changes in postsynaptic adenosine A(2A) receptors during early stages of a rat model of Huntington disease. Experimental Neurology, 232(1), 76–80.
Penney, J. B, Jr, & Young, A. B. (1982). Quantitative autoradiography of neurotransmitter receptors in Huntington disease. Neurology, 32(12), 1391–1395.
Pieper, H. C., Evert, B. O., Kaut, O., Riederer, P. F., Waha, A., & Wüllner, U. (2008). Different methylation of the TNF-alpha promoter in cortex and substantia nigra: Implications for selective neuronal vulnerability. Neurobiology of Disease, 32(3), 521–527.
Pietrzak, M., Rempala, G., Nelson, P. T., Zheng, J. J., & Hetman, M. (2011). Epigenetic silencing of nucleolar rRNA genes in Alzheimer’s disease. PLoS ONE, 6(7), e22585.
Popoli, P., Blum, D., Domenici, M. R., Burnouf, S., & Chern, Y. (2008). A critical evaluation of adenosine A2A receptors as potentially “druggable” targets in Huntington’s disease. Current Pharmaceutical Design, 14(15), 1500–1511.
Popoli, P., Pintor, A., Domenici, M. R., Frank, C., Tebano, M. T., Pèzzola, A., et al. (2002). Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: Possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum. The Journal of Neuroscience, 22(5), 1967–1975.
Reiner, A., Albin, R. L., Anderson, K. D., D’Amato, C. J., Penney, J. B., & Young, A. B. (1988). Differential loss of striatal projection neurons in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America, 85(15), 5733–5737.
Richfield, E. K., O’Brien, C. F., Eskin, T., & Shoulson, I. (1991). Heterogeneous dopamine receptor changes in early and late Huntington’s disease. Neuroscience Letters, 132(1), 121–126.
Saavedra, A., Garcia-Martinez, J. M., Xifro, X., Giralt, A., Torres-Peraza, J. F., Canals, J. M., et al. (2010). PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3 K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death and Differentiation, 17(2), 324–335.
Schiffmann, S. N., Fisone, G., Moresco, R., Cunha, R. A., & Ferré, S. (2007). Adenosine A2A receptors and basal ganglia physiology. Progress in Neurobiology, 83(5), 277–292.
Song, C. X., Szulwach, K. E., Fu, Y., Dai, Q., Yi, C., Li, X., et al. (2011). Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nature Biotechnology, 29(1), 68–72.
Steffan, J. S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y. Z., Gohler, H., et al. (2000). The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proceeding of the National Academy of Sciences of the United States of America, 97(12), 6763–6768.
Sunahori, K., Juang, Y. T., & Tsokos, G. C. (2009). Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. Journal of Immunology, 182(3), 1500–1508.
Suzuki, M. M., & Bird, A. (2008). DNA methylation landscapes: Provocative insights from epigenomics. Nature Review Genetics, 9(6), 465–476.
Szulwach, K. E., Li, X., Li, Y., Song, C. X., Wu, H., Dai, Q., et al. (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature Neuroscience, 14(12), 1607–1616.
Taherzadeh-Fard, E., Saft, C., Wieczorek, S., Epplen, J. T., & Arning, L. (2010). Age at onset in Huntington’s disease: Replication study on the associations of ADORA2A, HAP1 and OGG1. Neurogenetics, 11(4), 435–439.
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., et al. (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324(5929), 930–935.
Tebano, M. T., Martire, A., Chiodi, V., Ferrante, A., & Popoli, P. (2010). Role of adenosine A(2A) receptors in modulating synaptic functions and brain levels of BDNF: A possible key mechanism in the pathophysiology of Huntington’s disease. ScientificWorldJournal, 10, 1768–1782.
The Huntington’s Disease Collaborative Research Group. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6), 971–983.
Valinluck, V., & Sowers, L. C. (2007). Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Research, 67(12), 946–950.
Valinluck, V., Tsai, H. H., Rogstad, D. K., Burdzy, A., Bird, A., & Sowers, L. C. (2004). Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Research, 32(14), 4100–4108.
Van Ness, P. C., Watkins, A. E., Bergman, M. O., Tourtellotte, W. W., & Olsen, R. W. (1982). Gamma-Aminobutyric acid receptors in normal human brain and Huntington disease. Neurology, 32(1), 63–68.
Varani, K., Bachoud-Lévi, A. C., Mariotti, C., Tarditi, A., Abbracchio, M. P., Gasperi, V., et al. (2007). Biological abnormalities of peripheral A(2A) receptors in a large representation of polyglutamine disorders and Huntington’s disease stages. Neurobiology of Disease, 27(1), 36–43.
Varani, K., Vincenzi, F., Tosi, A., Gessi, S., Casetta, I., Granieri, G., et al. (2010). A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson’s disease. FASEB J, 24(2), 587–598.
Vonsattel, J. P. (2008). Huntington disease models and human neuropathology: similarities and differences. Acta Neuropathologica, 115(1), 55–69.
Vonsattel, J. P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D., & Richardson, E. P, Jr. (1985). Neuropathological classification of Huntington’s disease. Journal of Neuropathology and Experimental Neurology, 44(6), 559–577.
Weber, M., Hellmann, I., Stadler, M. B., Ramos, L., Pääbo, S., Rebhan, M., et al. (2007). Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics, 39(4), 457–466.
Whitehouse, P. J., Trifiletti, R. R., Jones, B. E., Folstein, S., Price, D. L., Snyder, S. H., et al. (1985). Neurotransmitter receptor alterations in Huntington’s disease: autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes. Annals of Neurology, 18(2), 202–210.
Xin, Y., O’Donnell, A. H., Ge, Y., Chanrion, B., Milekic, M., Rosoklija, G., et al. (2011). Role of CpG context and content in evolutionary signatures of brain DNA methylation. Epigenetics, 6(11), 1308–1318.
Yossifoff, M., Kisliouk, T., & Meiri, N. (2008). Dynamic changes in DNA methylation during thermal control establishment affect CREB binding to the brain-derived neurotrophic factor promoter. The European Journal of Neuroscience, 28(11), 2267–2277.
Young, A. B., Greenamyre, J. T., Hollingsworth, Z., Albin, R., D’Amato, C., Shoulson, I., et al. (1988). NMDA receptor losses in putamen from patients with Huntington’s disease. Science, 241(4868), 981–983.
Yu, L., Frith, M. C., Suzuki, Y., Peterfreund, R. A., Gearan, T., Sugano, S., et al. (2004). Characterization of genomic organization of the adenosine A2A receptor gene by molecular and bioinformatics analyses. Brain Research, 2004(1–2), 156–173.
Yu, Z. X., Li, S. H., Nguyen, H. P., & Li, X. J. (2002). Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice. Human Molecular Genetics, 11(8), 905–914.
Zuccato, C., Marullo, M., Conforti, P., MacDonald, M. E., Tartari, M., & Cattaneo, E. (2008). Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington’s disease. Brain Pathology, 18(2), 225–238.
Acknowledgments
We are grateful to Dr. Ellen Gelpí for providing HD cases (Neurological Tissue Bank, University of Barcelona—Hospital Clínic de Barcelona) and to Dr. Laura de Jorge (Molecular Genetic Diagnosis Center, IDIBELL) for technical advice in CAG repeat determination. We thank T. Yohannan for editorial assistance. This work was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III [CP08/00095 to M.B., PI10/01072 to E.P.N.]; and La Fundació La Marató de TV3 [090330 to M.B., 092331 to M.M.]. I.V.M. is the recipient of an IDIBELL predoctoral fellowship and S.T. is a fellow of the Generalitat de Catalunya (AGAUR ST06914).
Conflict of Interest
The authors declare no competing financial interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Izaskun Villar-Menéndez and Marta Blanch: contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Villar-Menéndez, I., Blanch, M., Tyebji, S. et al. Increased 5-Methylcytosine and Decreased 5-Hydroxymethylcytosine Levels are Associated with Reduced Striatal A2AR Levels in Huntington’s Disease. Neuromol Med 15, 295–309 (2013). https://doi.org/10.1007/s12017-013-8219-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-013-8219-0