title: Changes in cardiac nucleotide metabolism in Huntington's disease.
abstract: Huntington's disease (HD) is a monogenic neurodegenerative disorder with a significant peripheral component to the disease pathology. This includes an HD-related cardiomyopathy, with an unknown pathological mechanism. In this study, we aimed to define changes in the metabolism of cardiac nucleotides using the well-established R6/2 mouse model. In particular, we focused on measuring the activity of enzymes that control ATP and other adenine nucleotides in the cardiac pool, including eNTPD, AMPD, e5'NT, ADA, and PNP. We employed HPLC to assay the activities of these enzymes by measuring the concentrations of adenine nucleotide catabolites in the hearts of symptomatic R6/2 mice. We found a reduced activity of AMPD (12.9 ± 1.9 nmol/min/mg protein in control; 7.5 ± 0.5 nmol/min/mg protein in R6/2) and e5'NT (11.9 ± 1.7 nmol/min/mg protein in control; 6.7 ± 0.7 nmol/min/mg protein in R6/2). Moreover, we detected an increased activity of ADA (1.3 ± 0.2 nmol/min/mg protein in control; 5.2 ± 0.5 nmol/min/mg protein in R6/2), while no changes in eNTPD and PNP activities were observed. Analysis of cardiac adenine nucleotide catabolite levels revealed an increased inosine level (0.7 ± 0.01 nmol/mg dry tissue in control; 2.7 ±0.8 nmol/mg dry tissue in R6/2) and a reduced concentration of cardiac adenosine (0.9 ± 0.2 nmol/mg dry tissue in control; 0.2 ± 0.08 nmol/mg dry tissue in R6/2). This study highlights a decreased rate of degradation of cardiac nucleotides in HD mouse model hearts, and an increased capacity for adenosine deamination, that may alter adenosine signaling.
authors.affiliation: a Department of Biochemistry , Medical University of Gdańsk , Gdańsk , Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Toczek
authors.affiliation: a Department of Biochemistry , Medical University of Gdańsk , Gdańsk , Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kutryb-Zajac
authors.affiliation: a Department of Biochemistry , Medical University of Gdańsk , Gdańsk , Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Zukowska
authors.affiliation: a Department of Biochemistry , Medical University of Gdańsk , Gdańsk , Poland.
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Slominska
authors.affiliation: b Department of Life Sciences , Imperial College London , UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Isalan
authors.affiliation: b Department of Life Sciences , Imperial College London , UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Mielcarek
authors.affiliation: a Department of Biochemistry , Medical University of Gdańsk , Gdańsk , Poland.
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
mesh_terms: D000659:AMP Deaminase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007288:Inosine / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism
chemical_list: D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D000243:Adenosine Deaminase; D000659:AMP Deaminase; D011755:Pyrophosphatases; C439652:nucleoside-triphosphate diphosphohydrolase 3; D000241:Adenosine
keywords: AMP deaminase; HD-related cardiomyopathy; Huntington's disease; adenine nucleotides catabolism; adenosine deaminase