title: Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model.
abstract: Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that altered Mn bioavailability as a cofactor leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage, contributing to HD striatal urea-cycle pathophysiology through an effect on arginase activity.
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA; Vanderbilt Brain Institute, VU.
authors.forename: Terry Jo V
authors.initials: TJV
authors.lastname: Bichell
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Wegrzynowicz
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: K Grace
authors.initials: KG
authors.lastname: Tipps
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Bradley
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Uhouse
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA; Vanderbilt Brain Institute, VU.
authors.forename: Miles
authors.initials: M
authors.lastname: Bryan
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA; Vanderbilt Brain Institute, VU.
authors.forename: Kyle
authors.initials: K
authors.lastname: Horning
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fisher
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Karrie
authors.initials: K
authors.lastname: Dudek
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Halbesma
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Umashanker
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Stubbs
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Hunter K
authors.initials: HK
authors.lastname: Holt
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Kwakye
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tidball
authors.affiliation: Department of Molecular Physiology and Biophysics, VU, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA; Vanderbilt Brain Institute, VU.
authors.forename: M Diana
authors.initials: MD
authors.lastname: Neely
authors.affiliation: Centre for Neurogenetics and Rare Diseases, IRCCS Neuromed, Pozzilli, IS, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Di Pardo
authors.affiliation: Centre for Neurogenetics and Rare Diseases, IRCCS Neuromed, Pozzilli, IS, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Maglione
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Osmand
authors.affiliation: Department of Pediatrics, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Neurology, Vanderbilt University (VU), Vanderbilt University Medical Center (VUMC), Nashville, TN, USA; Department of Biochemistry, Vanderbilt University (VU), Nashville, TN, USA; Vanderbilt Brain Institute, VU. Electronic address: aaron.bowman@vanderbilt.edu.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D014508:Urea / Q000378:metabolism*
chemical_list: D008345:Manganese; D014508:Urea; C481673:Arg2 protein, mouse; D001119:Arginase
keywords: Arginase; Huntington's; Manganese; Neurodegeneration; Striatum; Urea