title: Reduced striatal adenosine A2A receptor levels define a molecular subgroup in schizophrenia.
abstract: Schizophrenia (SZ) is a mental disorder of unknown origin. Some scientific evidence seems to indicate that SZ is not a single disease entity, since there are patient groups with clear symptomatic, course and biomarker differences. SZ is characterized by a hyperdopaminergic state related to high dopamine D2 receptor activity. It has also been proposed that there is a hypoadenosynergic state. Adenosine is a nucleoside widely distributed in the organism with neuromodulative and neuroprotective activity in the central nervous system. In the brain, the most abundant adenosine receptors are A1R and A2AR. In the present report, we characterize the presence of both receptors in human postmortem putamens of patients suffering SZ with real time TaqMan PCR, western blotting and radioligand binding assay. We show that A1R levels remain unchanged with respect to age-matched controls, whereas nearly fifty percent of patients have reduced A2AR, at the transcriptional and translational levels. Moreover, we describe how DNA methylation plays a role in the pathological A2AR levels with the bisulfite-sequencing technique. In fact, an increase in 5-methylcytosine percentage in the 5' UTR region of ADORA2A was found in those SZ patients with reduced A2AR levels. Interestingly, there was a relationship between the A2A/β-actin ratio and motor disturbances as assessed with some items of the PANSS, AIMS and SAS scales. Therefore, there may be a subgroup of SZ patients with reduced striatal A2AR levels accompanied by an altered motor phenotype.
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Villar-Menéndez
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Díaz-Sánchez
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Blanch
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Albasanz
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Thais
authors.initials: T
authors.lastname: Pereira-Veiga
authors.affiliation: Banc de Teixits Neurològics-Parc Sanitari Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Monje
authors.affiliation: Banc de Teixits Neurològics-Parc Sanitari Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Spain.
authors.forename: Luis Maria
authors.initials: LM
authors.lastname: Planchat
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain; Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain.
authors.forename: Mairena
authors.initials: M
authors.lastname: Martín
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Spain. Electronic address: mbarrachina@idibell.cat.
authors.forename: Marta
authors.initials: M
authors.lastname: Barrachina
mesh_terms: D000199:Actins / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D002462:Cell Membrane / Q000000981:diagnostic imaging / Q000187:drug effects; D019175:DNA Methylation; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011180:Postmortem Changes; D011569:Psychiatric Status Rating Scales; D011699:Putamen / Q000187:drug effects / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics; D014970:Xanthines / Q000493:pharmacokinetics
chemical_list: D000199:Actins; D058916:Adenosine A1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D014316:Tritium; C051360:1,3-dipropyl-8-cyclopentylxanthine
keywords: 5-Methylcytosine; ADORA2A; Adenosine A(2A) receptor; Motor disturbances; PANSS; Postmortem; Putamen; Schizophrenia