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 (HIT), 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 Teduced 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 HIT 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. (C) 2017 The Author(s). Published by Elsevier B.V.
Bichell, Terry Jo. V., Michal Wegrzynowicz, K. Grace Tipps, et al. 2017. "Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1863(6): 1596-1604.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Huntington's, Neurodegeneration, Manganese, Arginase, Striatum, Urea