Huntingtonâs disease (HD) is caused by an increase in CAG repeats in exon 1 of the huntingtin gene (HTT), which results in a polyglutamine expansion in the HTT protein. This mutation causes profound striatal neurodegeneration through an unknown mechanism, which adversely affects multiple cellular processes including DNA repair, autophagy, vesicular transport and neuronal metal homeostasis. Many neuronal enzymes require metals as cofactors, including several within the partial urea cycle which functions in brain. 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) not Arginase 1 (ARG1) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure without change in gene expression levels. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that it is the altered Mn bioavailability as a cofactor that 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. This Mn deficiency contributes to HD striatal urea-cycle pathophysiology through an effect on ARG2.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12052016-221132 |
| Date | 06 December 2016 |
| Creators | Bichell, Terry Jo Vetters |
| Contributors | Aaron Blaine Bowman, Kaylon Bruner-Tran, Michael Aschner, Roger Colbran |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12052016-221132/ |
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