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NeuroMolecular Medicine

, Volume 15, Issue 2, pp 295–309 | Cite as

Increased 5-Methylcytosine and Decreased 5-Hydroxymethylcytosine Levels are Associated with Reduced Striatal A2AR Levels in Huntington’s Disease

  • Izaskun Villar-Menéndez
  • Marta Blanch
  • Shiraz Tyebji
  • Thais Pereira-Veiga
  • José Luis Albasanz
  • Mairena Martín
  • Isidre Ferrer
  • Esther Pérez-Navarro
  • Marta BarrachinaEmail author
Original Paper

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.

Keywords

Adenosine A2A receptor ADORA2A 5-Methylcytosine 5-Hydroxymethylcytosine Huntington’s disease 

Notes

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.

Supplementary material

12017_2013_8219_MOESM1_ESM.tif (578 kb)
Supplementary material 1 (The same analysis shown in Figure 6 was carried with HD cases (A) HD7, (B) HD8, and (C) HD10)

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Izaskun Villar-Menéndez
    • 1
  • Marta Blanch
    • 1
  • Shiraz Tyebji
    • 2
    • 3
    • 4
  • Thais Pereira-Veiga
    • 1
  • José Luis Albasanz
    • 5
    • 6
  • Mairena Martín
    • 5
    • 6
  • Isidre Ferrer
    • 1
    • 4
    • 7
  • Esther Pérez-Navarro
    • 2
    • 3
    • 4
  • Marta Barrachina
    • 1
    • 4
    Email author
  1. 1.Institute of Neuropathology, Bellvitge University Hospital‐ICS(Bellvitge Biomedical Research Institute‐) IDIBELLL’Hospitalet de LlobregatSpain
  2. 2.Facultad de Medicina, Departament de Biologia Cel.lular, Immunologia i NeurociènciesUniversitat de BarcelonaBarcelonaSpain
  3. 3.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  4. 4.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNEDMadridSpain
  5. 5.Facultad de Ciencia y Tecnologías Químicas, Departamento de Química Inorgánica, Orgánica y Bioquímica, Centro Regional de Investigaciones Biomédicas (CRIB)Universidad de Castilla-La ManchaCiudad RealSpain
  6. 6.Facultad de Medicina de Ciudad Real, Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIBUniversidad de Castilla-La ManchaCiudad RealSpain
  7. 7.Departament de Patologia i Terapèutica ExperimentalUniversitat de BarcelonaL’Hospitalet de LlobregatSpain

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