期刊
NEUROBIOLOGY OF DISEASE
卷 69, 期 -, 页码 206-214出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.05.030
关键词
Adenosine A(2A) receptor; ADORA2A; miR-34b; Putamen; Parkinson's disease; Post-mortem
资金
- Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III (ISCIII) [CP08/00095]
- Ministerio de Economia y Competitividad [BFU2011-23034]
Adenosine A(2A) receptor (A(2A)R) is a G-protein coupled receptor that stimulates adenylyl cyclase activity. In the brain, A(2A)Rs are found highly enriched in striatal GABAergic medium spiny neurons, related to the control of voluntary movement. Pharmacological modulation of A(2A)Rs is particularly useful in Parkinson's disease (PD) due to their property of antagonizing dopamine D-2 receptor activity. Increases in A(2A)R levels have been described in PD patients showing an important loss of dopaminergic denervation markers, but no data have been reported about A(2A)R levels in incidental PD brains. In the present report, we show that increased A(2A)Rs 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, A(2A)Rs mRNA levels remained unchanged, suggesting that posttranslational mechanisms could be involved in the regulation of A(2A)Rs. 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 A(2A)R contains a predicted target site for miR-34b, the potential role of this miRNA in protein A(2A)R levels was assessed. In vitro studies revealed that endogenous A(2A)R 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 A(2A)R 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 A(2A)R protein levels occur in asymptomatic PD patients and provide new insights into the molecular mechanisms underlying A(2A)R expression levels along the progression of this neurodegenerative disease. (C) 2014 Elsevier Inc. All rights reserved.
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