Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease

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

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.

MeSH terms

  • Adenosine / metabolism
  • Adenosine A2 Receptor Antagonists / therapeutic use
  • Animals
  • Biomarkers / metabolism*
  • Corpus Striatum / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / complications
  • Huntington Disease / genetics
  • Huntington Disease / pathology*
  • Locomotion / genetics
  • Nucleoside Transport Proteins / metabolism*
  • Prefrontal Cortex / metabolism*
  • Psychomotor Disorders / drug therapy
  • Psychomotor Disorders / etiology
  • Purines / therapeutic use
  • Rats
  • Rats, Transgenic
  • Receptor, Adenosine A2A / metabolism
  • Triazines / pharmacokinetics
  • Triazoles / pharmacokinetics
  • Trinucleotide Repeat Expansion / genetics
  • Tritium / pharmacokinetics

Substances

  • Adenosine A2 Receptor Antagonists
  • Biomarkers
  • Htt protein, rat
  • Huntingtin Protein
  • Nucleoside Transport Proteins
  • Purines
  • Receptor, Adenosine A2A
  • Triazines
  • Triazoles
  • ZM 241385
  • Tritium
  • istradefylline
  • Adenosine