Deletion of equilibrative nucleoside transporter 2 disturbs energy metabolism and exacerbates disease progression in an experimental model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by motor dysfunction and abnormal energy metabolism. Equilibrative nucleoside transporter 1 (ENT1) and ENT2 are the major nucleoside transporters in cellular plasma membrane of the brain. Yet, unlike ENT1 whose function has been better investigated in HD, the role of ENT2 in HD remains unclear. The present study aimed to investigate the impacts of ENT2 deletion on HD using a well-characterized mouse model (R6/2). Microarray analysis, quantitative real-time polymerase chain reaction, and immunostaining of ENT2 in postmortem human brain tissues were conducted. R6/2 mice with or without genetic deletion of ENT2 were generated. Motor functions, including rotarod performance and limb-clasping test, were examined at the age of 7 to 12 weeks. Biochemical changes were evaluated by immunofluorescence staining and immunoblotting at the age of 12 to 13 weeks. In regard to energy metabolism, levels of striatal metabolites were determined by liquid chromatography coupled with the fluorescence detector or quadrupole time-of-flight mass spectrometer. Mitochondrial bioenergetics was assessed by the Seahorse assay. The results showed that ENT2 protein was detected in the neurons and astrocytes of human brains and the levels in the postmortem brain tended to be higher in patients with HD. In mice, ENT2 deletion did not alter the phenotype of the non-HD controls. Yet, ENT2 deletion deteriorated motor function and increased the number of aggregated mutant huntingtin in the striatum of R6/2 mice. Notably, disturbed energy metabolism with decreased ATP level and increased AMP/ ATP ratio was observed in R6/2-Ent2

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Declaration of Competing Interest The authors declare no competing interests.