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On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

ABSTRACT: Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice striata, and in the latter we could also observe a consistent reduction in DNA methylation at gene promoter and an increase in histone H3 acetylation at lysine 9. Of particular relevance in clinical samples, we also observed higher levels in the receptor gene expression in younger subjects, as well as in those with less years from disease onset, and less severe disease according to clinical scores. In conclusion, the present findings provide further evidence of the relevant role of A2AR in PD and, based on the clinical data, highlight its potential role as disease biomarker for PD especially at the initial stages of disease development. Furthermore, our preclinical results also suggest selective epigenetic mechanisms targeting gene promoter as tool for the development of new treatments.

SUBMITTER: Falconi A

PROVIDER: S-EPMC6635589 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

Falconi Anastasia A Bonito-Oliva Alessandra A Di Bartolomeo Martina M Massimini Marcella M Fattapposta Francesco F Locuratolo Nicoletta N Dainese Enrico E Pascale Esterina E Fisone Gilberto G D'Addario Claudio C

Frontiers in neuroscience 20190710

Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice ...[more]

PMID: 31354407

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Project description:ObjectivePharmacological activation of adenosine signaling has been shown to increase ?-cell proliferation and thereby ?-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating ?-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates ?-cell proliferation-either in the basal state or states of increased demand for insulin-and to delineate the mechanisms involved.MethodsWe analyzed the effect of pharmacological adenosine agonists on ?-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with ?- or ?-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas- or ?-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets.ResultsPharmacological adenosine signaling in zebrafish had a stronger effect on ?-cell proliferation during ?-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory ?-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of ?-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse ?-cells in vitro.ConclusionsThis is the first study linking endogenously produced adenosine to ?-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory ?-cell proliferation, a feature that could be harnessed pharmacologically for ?-cell expansion and future therapeutic development for diabetes.

Project description:BackgroundMacrophage exosomes and vascular endothelial cells (VECs) are critical to bone healing. However, few studies explore the molecular regulation of them in the bone fracture microenvironment.MethodsIn this study, we explored the effects of adenosine receptor A2A (ADA2AR) in macrophage exosomes and VECs during bone healing. CGS21680 (an ADA2AR agonist) and ZM241385 (an ADA2AR antagonist) were used. First, the effects of the ADA2AR on VECs during bone healing were studied in vivo in a rat tibial fracture model. Second, the effects of ADA2AR on VECs and in the regulation of VECs by macrophages were examined in the bone fracture microenvironment. Third, the effects of ADA2AR on the regulation of macrophage exosomes on VECs were analyzed. Finally, the genes and long non-coding RNAs (lncRNAs) associated with the regulation of VECs by the ADA2AR were examined by high-throughput sequencing and bioinformatics analysis.ResultsCGS21680 accelerated VEC proliferation in the early stage of bone healing and that ZM241385 suppressed VEC proliferation in vivo. ZM241385 inhibited cell viability and tube formation in vitro. However, CGS21680 did not promote tube formation, cell proliferation, or cell migration in vitro. The inhibition of macrophage exosomes could suppress tube formation and VEC migration. CGS21680 had no effects on tube formation in a macrophage-VEC co-culture. The macrophage exosomes were purified and CGS21680 promoted the macrophage secretion of exosomes. In contrast, ZM241385 inhibited the macrophage secretion exosomes. Finally, the lncRNA and mRNA involved in the activation of the ADA2AR in VECs were analyzed. CGS21680 upregulated 3274 mRNAs and downregulated 2236 mRNAs, and upregulated 1696 lncRNAs and downregulated 1882 lncRNAs. The hub genes involved in angiogenesis were Flt1, Fgf2, Mapk14, Fn1, and Jun.ConclusionThe activation of ADA2AR was essential for angiogenesis and the secretion of exosomes by macrophages during bone healing; moreover, the inactivation of the ADA2AR led to poor angiogenesis and bone nonunion.

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On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

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On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

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