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Colbran Lab

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

AUTHORS

Bichell TJTerry Jo V , Wegrzynowicz MMichal , Grace Tipps KK , Bradley EMEmma M , Uhouse MAMichael A , Bryan MMiles , Horning KKyle , Fisher NNicole , Dudek KKarrie , Halbesma TTimothy , Umashanker PPreethi , Stubbs ADAndrew D , Holt HKHunter K , Kwakye GFGunnar F , Tidball AMAndrew M , Colbran RJRoger J , Aschner MMichael , Diana Neely MM , Di Pardo AAlba , Maglione VVittorio , Osmand AAlexander , Bowman ABAaron B . Biochimica et biophysica acta. 2017 2 14; ().

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.