ArticleBiochimica et biophysica acta. Molecular basis of disease2017
Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model.
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Article in Biochimica et biophysica acta. Molecular basis of disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28citing papers in PubMed
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28 citing papers in PubMed, 43 citations in OpenAlex.
- DNA methylation profiling in Huntington's disease reveals disease associated changes in the striatum.Clinical epigenetics · 2026Article
- Vitamin C Transport Deficiency Alters Striatal Dopamine Gene Expression and Metabolism in YAC128 Huntington Disease Mice.Genes, brain, and behavior · 2025Article
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Article
- Alterations in Cerebrospinal Fluid Urea Occur in Late Manifest Huntington's Disease.Journal of Huntington's disease · 2024Article
- Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Alterations in metal homeostasis occur prior to canonical markers in Huntington disease.Scientific reports · 2022Article
- Non-invasive radionuclide imaging of trace metal trafficking in health and disease: "PET metallomics".RSC chemical biology · 2022Review
- YAC128 mouse model of Huntington disease is protected against subtle chronic manganese (Mn)-induced behavioral and neuropathological changes.Neurotoxicology · 2021Article
- Multiplatform metabolomic analysis of the R6/2 mouse model of Huntington's disease.FEBS open bio · 2021Article
- Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update.International journal of molecular sciences · 2021Review
- The Impact of Environmental Factors on Monogenic Mendelian Diseases.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Identification of Three Small Molecules That Can Selectively Influence Cellular Manganese Levels in a Mouse Striatal Cell Model.Molecules (Basel, Switzerland) · 2021Article
- Manganese-induced neurodegenerative diseases and possible therapeutic approaches.Expert review of neurotherapeutics · 2020Review
- The impact of manganese on neurotransmitter systems.Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2020Review
- Manganese-induced Mitochondrial Dysfunction Is Not Detectable at Exposures Below the Acute Cytotoxic Threshold in Neuronal Cell Types.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice.Metallomics : integrated biometal science · 2020Article
- Identification of a selective manganese ionophore that enables nonlethal quantification of cellular manganese.The Journal of biological chemistry · 2020Article
- Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.Molecular neurobiology · 2020Article
- The Role of Autophagy in Manganese-Induced Neurotoxicity.Frontiers in neuroscience · 2020Review
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Authors and funding
22 authors at 6 institutions in 2 countries.
Terry Jo V BichellDepartment 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.
Michal WegrzynowiczDepartment 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.
K Grace TippsDepartment 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.
Emma M BradleyDepartment 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.
Michael A UhouseDepartment 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.
Miles BryanDepartment 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.
Kyle HorningDepartment 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.
Nicole FisherDepartment 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.
Karrie DudekDepartment 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.
Timothy HalbesmaDepartment 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.
Preethi UmashankerDepartment 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.
Andrew D StubbsDepartment 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.
Hunter K HoltDepartment 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.
Gunnar F KwakyeDepartment 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.
Andrew M TidballDepartment 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.
Roger J ColbranDepartment of Molecular Physiology and Biophysics, VU, USA.
Michael AschnerDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
M Diana NeelyDepartment 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.
Alba Di PardoCentre for Neurogenetics and Rare Diseases, IRCCS Neuromed, Pozzilli, IS, Italy.
Vittorio MaglioneCentre for Neurogenetics and Rare Diseases, IRCCS Neuromed, Pozzilli, IS, Italy.
Alexander OsmandDepartment of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA.
Aaron B BowmanDepartment 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.
Vanderbilt University Medical Center · USVanderbilt University · USAllen Institute for Brain Science · USIstituto Neurologico Mediterraneo · ITAlbert Einstein College of Medicine · USUniversity of Tennessee at Knoxville · US
Funding
TRAINING PROGRAM IN ENVIRONMENTAL TOXICOLOGYT32ES007028 · NIEHS · VANDERBILT UNIVERSITY · PI F PETER Guengerich, Fiona Edith Harrison · 1985 to 2026
$15.7MMechanisms of Manganese NeurotoxicityR01ES010563 · NIEHS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI Michael Aschner, Aaron B Bowman · 2001 to 2026
$11.9MTRAINING IN PHARMACOLOGICAL SCIENCEST32GM007628 · NIGMS · VANDERBILT UNIVERSITY · PI BARNETT, JOEY VICTOR, KAVALALI, EGE T · 1985 to 2022
$11.2MResearch Project: Sensory and Multisensory Contributions to AutismU54HD083211 · NICHD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI DYKENS, ELISABETH MAY · 2015 to 2019
$7.1MGene-Neurotoxicant Interactions in Huntington DiseaseR01ES016931 · NIEHS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BOWMAN, AARON B · 2008 to 2018
$4.5MExploring Disease-Toxicant Interactions in a Human Huntington's Disease ModelF31NS077632 · NINDS · VANDERBILT UNIVERSITY · PI TIDBALL, ANDREW M · 2012 to 2014
$61kNICHD NIH HHS U54 HD083211NIEHS NIH HHS R01 ES010563NIEHS NIH HHS R01 ES016931NIEHS NIH HHS T32 ES007028NIGMS NIH HHS T32 GM007628NINDS NIH HHS F31 NS077632
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.
Indexed as
AnimalsArginaseCorpus StriatumDisease Models, AnimalHuntington DiseaseMaleManganeseMiceNeuronsUreaArg2 protein, mouseArginaseManganeseUreaArginaseHuntington'sManganeseNeurodegenerationStriatumUrea
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