Elevated levels of metals, including manganese (Mn), iron, and copper, have been associated with motor disease. These metals have been shown to accumulate in the basal ganglia and buildup is associated with motor deficits. However, chelating therapeutics are not as effective, suggesting that metal toxicity might induce microenvironmental changes contributing to motor deficits.
It is well known that kynurenine pathway (KP) metabolites can play a role in inflammation (quinolinic acid (QUIN), and 3-hydroxykynurenine (3-HK)), oxidative stress (QUIN), and neurotoxicity (QUIN, 3-HK, and 3-HAA) which may lead to degeneration and play a role in neuromuscular decline (see 2023 April Highlight). Alternatively, upregulation of KP and enhanced kynurenine-AhR signaling can disrupt energy homeostasis, thereby contributing to the development of neurodegeneration (see 2024 August Highlight). In a recent study published by Dr. Somshuvra Mukhopadhyay’s group which focused on metal toxicity and hypoxia-inducible factor (HIF) 1 and HIF2 activation, they identified by combined unbiased transcriptomics and metabolomics analyses that KP upregulation contributes to the pathophysiology of metal overload-induced motor deficits.
In this study, mice were given Mn at different ages to mimic human exposure at different life stages, including infancy, childhood, and adolescence. Untargeted transcriptomic analysis revealed that Mn-exposure upregulated metabolic associated genes in the brain including tryptophan metabolism genes tryptophan 2,3 dioxygenase (TDO2), kynureninase, and 3-hydroxyanthranilic acid 3,4 dioxygenase. These enzymes drive changes in KP metabolite levels. Indeed, untargeted metabolomics showed that kynurenine levels were significantly increased, while NAD+ and xanthurenic acid levels were decreased in the brains of early postnatal mice exposed to Mn. Similarly, liver kynurenine, anthranilic acid, and kynurenic acid levels were increased after Mn-exposure. Since kynurenine can cross the blood-brain barrier, increased liver levels can further contribute to the dysregulation of the KP in the brain. Interestingly, therapeutic TDO inhibitors prevented the upregulation of TDO2 in Mn-exposed animals and improved motor function.
This model demonstrates that the KP may underlie the pathophysiology of Mn-induced motor deficits. Furthermore, TDO2 inhibitor therapeutics in combination with chelating drugs may be a plausible treatment option for metal-induced motor deficits, however, additional research is needed to investigate the safety and efficacy of this co-therapy option.