Untargeted metabolic profiling identifies interactions between Huntington's disease and neuronal manganese status

Abstract

Manganese (Mn) is an essential micronutrient for development and function of the nervous system. Deficiencies in Mn transport have been implicated in the pathogenesis of Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder characterized by loss of medium spiny neurons of the striatum. Brain Mn levels are highest in striatum and other basal ganglia structures, the most sensitive brain regions to Mn neurotoxicity. Mouse models of HD exhibit decreased striatal Mn accumulation and HD striatal neuron models are resistant to Mn cytotoxicity. We hypothesized that the observed modulation of Mn cellular transport is associated with compensatory metabolic responses to HD pathology. Here we use an untargeted metabolomics approach by performing ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) on control and HD immortalized mouse striatal neurons to identify metabolic disruptions under three Mn exposure conditions, low (vehicle), moderate (non-cytotoxic) and high (cytotoxic). Our analysis revealed lower metabolite levels of pantothenic acid, and glutathione (GSH) in HD striatal cells relative to control cells. HD striatal cells also exhibited lower abundance and impaired induction of isobutyryl carnitine in response to increasing Mn exposure. In addition, we observed induction of metabolites in the pentose shunt pathway in HD striatal cells after high Mn exposure. These findings provide metabolic evidence of an interaction between the HD genotype and biologically relevant levels of Mn in a striatal cell model with known HD by Mn exposure interactions. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathobiology of both HD and Mn neurotoxicity.

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

“…However, iron toxicity resulting from altered cellular distribution of iron within neurons and glial cells, which would not be detected by the ICP-MS methodology used, cannot be discounted by our data. Copper and manganese have both been implicated in HD pathogenesis [5, 32–34]. Copper and manganese can interact with iron during development [35, 36].…”

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

“…Recent technological advances in this field has allowed the discovery of new biomarkers of diseases such as coronary artery disease, septic shock and brain tumors as well as the discovery of new drugs 1-5 . Metabolomic analysis has also deepened our understanding of several disease models, leading to the discovery of new pathways or targets for drug therapies that could later be applied to the treatment of various diseases [6][7][8][9][10][11] . Indeed, metabolomics are closer to the phenotype of a given disease compared with transcriptomic or proteomic analysis, both of which are prone to downstream modifications and changes in activities 1,12 .Several techniques, tools and software platforms exist to study metabolomics, all of which complement each other 13 .…”

Metabolomics of Neurodegenerative Diseases

“…and most were in animal models of the disease (Tsang et al, 2006;Underwood et al, 2006;Verwaest et al, 2011). The most recent study (Kumar et al, 2015) indicates the role of manganese in pathophysiology of HD and supports the observation that there is an impairment of energy metabolism in HD that ultimately affects the function of neurons. Metabolomics studies in HD thus are driven more toward hypothesis generation for disease pathology and potential treatment rather than toward finding diagnostic biomarkers.…”