title: Targeting ENT1 and adenosine tone for the treatment of Huntington's disease.
abstract: Huntington's disease (HD) is caused by an abnormal CAG expansion in the exon 1 of huntingtin gene. The treatment of HD is an unmet medical need. Given the important role of adenosine in modulating brain activity, in this study, levels of adenosine and adenine nucleotides in the cerebral spinal fluid of patients with HD and in the brain of two mouse models of HD (R6/2 and Hdh150Q) were analysed. The expression and activity of ENT1 in the striatum of mice with HD were measured. Targeting adenosine tone for treating HD was examined in R6/2 mice by genetic removal of ENT1 and by giving an ENT1 inhibitor, respectively. The results showed that the adenosine homeostasis is dysregulated in the brain of patients and mice with HD. In patients, the ratio of adenosine/ATP in the cerebral spinal fluid was negatively correlated with the disease duration, and tended to have a positive correlation with independence scale and functional capacity. In comparison to controls, mRNA level of ENT1 was higher in the striatum of R6/2 and Hdh150Q mice. Intrastriatal administration of ENT1 inhibitors increased extracellular level of adenosine in the striatum of R6/2 mice to a much higher level than controls. Chronic inhibition of ENT1 or by genetic removal of ENT1 enhanced the survival of R6/2 mice. Collectively, adenosine homeostasis and ENT1 expression are altered in HD. The inhibition of ENT1 can enhance extracellular adenosine level and be a potential therapeutic approach for treating HD.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Meng-Syuan
authors.initials: MS
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsing-Lin
authors.initials: HL
authors.lastname: Lai
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
mesh_terms: D000225:Adenine / Q000134:cerebrospinal fluid / Q000378:metabolism; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; C086055:HTT protein, human; D000071058:Huntingtin Protein; D007211:Indoles; C000610187:N6-(3-indolylethyl)adenosine; C438649:SLC29A1 protein, human; C486681:Slc29a2 protein, mouse; D000225:Adenine; D000241:Adenosine