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Neurobiol Dis. 2016 Dec;96:47-53. doi: 10.1016/j.nbd.2016.08.013. Epub 2016 Aug 24.

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.

Author information

1
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.
2
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy.
3
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.
4
Division of Neuroscience Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
5
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.
6
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.

Abstract

The initial goal of this study was to investigate alterations in adenosine A2A receptor (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.

KEYWORDS:

A(2A) receptor; Adenosine; ENT1; Huntington disease

PMID:
27567601
PMCID:
PMC5102769
DOI:
10.1016/j.nbd.2016.08.013
[Indexed for MEDLINE]
Free PMC Article

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