Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease

NEUROBIOLOGY OF DISEASE

卷:96

Article

Guitart, Xavier¹  Bonaventura, Jordi¹  Rea, William¹  Orru, Marco¹  Cellai, Lucrezia²  Dettori, Ilaria²  Pedata, Felicita²  Brugarolas, Marc^3,4,5  Cortes, Antonio^3,4,5  Casado, Vicent^3,4,5  Chang, Ching-Pang⁶  Narayanan, Manikandan⁷  Chern, Yijuang⁶  Ferre, Sergi¹ 

[1] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA

[2] Univ Florence, Div Pharmacol & Toxicol, Dept NEUROFARBA, I-50139 Florence, Italy

[3] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain

[4] Ctr Biomed Res Neurodegenerat Dis Network, Barcelona 08028, Spain

[5] Inst Biomed, Barcelona 08028, Spain

[6] Acad Sinica, Div Neurosci, Inst Biomed Sci, Taipei 11529, Taiwan

[7] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, Intramural Res Program,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

关键词: Adenosine;    ENT1;    A(2A) receptor;    Huntington disease;   

DOI  :  10.1016/j.nbd.2016.08.013

来源: Elsevier

【 摘 要 】

The initial goal of this study was to investigate alterations in adenosine A(2A) receptor (A(2A)R) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENTI) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [H-3]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENTI binding sites were significantly upregulated in zQl 75 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENTI transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENTI and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease. Published by Elsevier Inc.

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