title: Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.
abstract: The initial goal of this study was to investigate alterations in adenosine A2Areceptor (A2AR) 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 (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [3H]-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 ENT1 binding sites were significantly upregulated in zQ175 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. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 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.
authors: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.
authors: Xavier
authors: X
authors: Guitart
authors: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.
authors: Jordi
authors: J
authors: Bonaventura
authors: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.
authors: William
authors: W
authors: Rea
authors: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.
authors: Marco
authors: M
authors: Orrú
authors: Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy.
authors: Lucrezia
authors: L
authors: Cellai
authors: Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy.
authors: Ilaria
authors: I
authors: Dettori
authors: Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy.
authors: Felicita
authors: F
authors: Pedata
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine, 08028 Barcelona, Spain.
authors: Marc
authors: M
authors: Brugarolas
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine, 08028 Barcelona, Spain.
authors: Antonio
authors: A
authors: Cortés
authors: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine, 08028 Barcelona, Spain.
authors: Vicent
authors: V
authors: Casadó
authors: Division of Neuroscience Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
authors: Ching-Pang
authors: CP
authors: Chang
authors: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, United States.
authors: Manikandan
authors: M
authors: Narayanan
authors: Division of Neuroscience Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
authors: Yijuang
authors: Y
authors: Chern
authors: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States. Electronic address: sferre@intra.nida.nih.gov.
authors: Sergi
authors: S
authors: Ferré
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008124:Locomotion / Q000235:genetics; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D011596:Psychomotor Disorders / Q000188:drug therapy / Q000209:etiology; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D055647:Rats, Transgenic; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D015415:Biomarkers; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D033703:Nucleoside Transport Proteins; D011687:Purines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D014316:Tritium; C111599:istradefylline; D000241:Adenosine
keywords: A(2A) receptor; Adenosine; ENT1; Huntington disease