title: Increased striatal adenosine A2A receptor levels is an early event in Parkinson's disease-related pathology and it is potentially regulated by miR-34b.
abstract: Adenosine A2A receptor (A2AR) is a G-protein coupled receptor that stimulates adenylyl cyclase activity. In the brain, A2ARs are found highly enriched in striatal GABAergic medium spiny neurons, related to the control of voluntary movement. Pharmacological modulation of A2ARs is particularly useful in Parkinson's disease (PD) due to their property of antagonizing dopamine D2 receptor activity. Increases in A2AR levels have been described in PD patients showing an important loss of dopaminergic denervation markers, but no data have been reported about A2AR levels in incidental PD brains. In the present report, we show that increased A2ARs protein levels were also detected in the putamen of incidental PD cases (Braak PD stages 1-2) with respect to age-matched controls. By contrast, A2ARs mRNA levels remained unchanged, suggesting that posttranslational mechanisms could be involved in the regulation of A2ARs. It has been described how miR-34b/c downregulation is an early event in PD cases. We found that miR-34b levels are also significantly reduced in the putamen of incidental PD cases and along disease progression. Given that 3'UTR of A2AR contains a predicted target site for miR-34b, the potential role of this miRNA in protein A2AR levels was assessed. In vitro studies revealed that endogenous A2AR protein levels increased when miR-34b function was blocked using a specific anti-miR-34b. Moreover, using a luciferase reporter assay with point mutations in a miR-34b predicted binding site within the 3'UTR region of A2AR mRNA abolished the effect of the miRNA using a miR-34b mimic. In addition, we showed a reduced percentage of DNA methylation in the 5'UTR region of ADORA2A in advanced PD cases. Overall, these findings reveal that increased A2AR protein levels occur in asymptomatic PD patients and provide new insights into the molecular mechanisms underlying A2AR expression levels along the progression of this neurodegenerative disease.
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: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Porta
authors.affiliation: Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: Buira
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: Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias 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: Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias 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; 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 Ciencias 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: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010300:Parkinson Disease / Q000503:physiopathology*; D011699:Putamen / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A
keywords: ADORA2A; Adenosine A(2A) receptor; Parkinson’s disease; Post-mortem; Putamen; miR-34b