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

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.

The Arginase Pathway in Neonatal Brain Hypoxia-Ischemia

“…Considering that M2-microglia have been shown to elicit beneficial effects in the injured brain [138], these findings suggest modulating ARG expression after HI could have beneficial effects especially via microglial polarization amongst others. ARG catalytic function may be supported by manganese (Mn) administration as shown in studies with a mouse model of Huntington disease, where Mn supplementation increased ARG-2 activity [139].…”

Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes

“…This inflammatory response increases expression of yin yang-1, a transcription repressor that inhibits production of excitatory amino acid transporter-2, which is necessary for glutamate reuptake (Karki et al, 2015; Karki et al, 2014). Recent studies also demonstrate that Mn interferes with neurodegenerative disease-specific proteins including prions, alpha-synuclein and huntingtin (Bichell et al, 2017; Choi et al, 2010; Choi et al, 2007; Harischandra et al, 2015), as well as protein misfolding, which may further contribute to neuroinflammation. Thus, Mn exposure can activate the inflammatory response in astrocytes, which can further contribute to Mn neurotoxicity.…”

Putrescine as indicator of manganese neurotoxicity: Dose-response study in human SH-SY5Y cells

“…Secondly, the results establish a Mn-dependent increase in putrescine, but additional studies will be needed to understand the time course of effects, especially taking into account possible time-dependent variations in Mn concentration in subcellular compartments, and in different neuronal and non-neuronal cell lines. The limited information on human cells that exists shows that Mn increased polyamine uptake by breast cancer cells (Poulin et al, 1995), altered arginase activity in a Huntington disease mouse model (Bichell et al, 2017), and increased arignase activity and putrescine levels in bovine coronary ventricular endothelial cells (Li et al, 2001). Thirdly, the correlation of metabolites with putrescine do not establish causal relationships between the metabolites, and additional studies will be needed to establish such relationships.…”