Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

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 ure...

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Published in:	Biochimica et biophysica acta. Molecular basis of disease Vol. 1863; no. 6; pp. 1596 - 1604
Main Authors:	Bichell, Terry Jo V., Wegrzynowicz, Michal, Tipps, K. Grace, Bradley, Emma M., Uhouse, Michael A., Bryan, Miles, Horning, Kyle, Fisher, Nicole, Dudek, Karrie, Halbesma, Timothy, Umashanker, Preethi, Stubbs, Andrew D., Holt, Hunter K., Kwakye, Gunnar F., Tidball, Andrew M., Colbran, Roger J., Aschner, Michael, Neely, M. Diana, Di Pardo, Alba, Maglione, Vittorio, Osmand, Alexander, Bowman, Aaron B.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-06-2017
Subjects:	Animals Arginase Arginase - metabolism Corpus Striatum - metabolism Corpus Striatum - pathology Disease Models, Animal Huntington Disease - metabolism Huntington Disease - pathology Huntington's Male Manganese Manganese - metabolism Mice Neurodegeneration Neurons - metabolism Neurons - pathology Striatum Urea Urea - metabolism Striatum Urea Arginase Neurodegeneration Huntington's Manganese
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Summary:	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. [Display omitted] •Metabolites of the urea cycle are altered in Huntington's model striata.•Exposure to manganese ameliorates urea cycle alterations.•Reduced enzymatic activity of arginase 2, is rescued with exposure to the co-factor.•Exposure to manganese increases arginase2 protein without increasing gene expression.•Baseline reductions in arginase 2 are revealed as disease progresses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0925-4439 1879-260X
DOI:	10.1016/j.bbadis.2017.02.013