Abstract
Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn-induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induced neurodegeneration using astrocyte culture as: (1) Astrocytes are vital for information processing within the brain, (2) their redox potential is essential in mitigating reactive oxygen species (ROS) levels, and (3) they are targeted early in the course of Mn toxicity. We first tested protein levels of Mn superoxide dismutase -2 (SOD-2) and glutathione peroxidase (GPx-1) as surrogates of astrocytic oxidative stress response. We assessed levels of the forkhead winged-helix transcription factor O (FoxO) in response to Mn exposure. FoxO is highly regulated by the insulin-signaling pathway. FoxO mediates cellular responses to toxic stress and modulates adaptive responses. We hypothesized that FoxO is fundamental in mediating oxidative stress response upon Mn treatment, and may be a biomarker of Mn-induced neurodegeneration. Our results indicate that 100 or 500 µM of MnCl2 led to increased levels of FoxO (dephosphorylated and phosphorylated) compared with control cells (P<0.01). p-FoxO disappeared from the cytosol upon Mn exposure. Pre-treatment of cultured cells with (R)-(−)-2-oxothiazolidine-4-carboxylic acid (OTC), a cysteine analog rescued the cytosolic FoxO. At these concentrations, MAPK phosphorylation, in particular p38 and ERK, and PPAR gamma coactivator-1 (PGC-1) levels were increased, while AKT phosphorylation remained unchanged. FoxO phosphorylation level was markedly reduced with the use of SB203580 (a p38 MAPK inhibitor) and PD98059 (an ERK inhibitor). We conclude that FoxO phosphorylation after Mn exposure occurs in parallel with, and independent of the insulin-signaling pathway. FoxO levels and its translocation into the nucleus are part of early events compensating for Mn-induced neurotoxicity and may serve as valuable targets for neuroprotection in the setting of Mn-induced neurodegeneration.
Highlights
Environmental exposure to manganese (Mn) leads to manganism, characterized by dopaminergic (DAergic) neurodegeneration, with clinical findings in humans that are reminiscent of idiopathic Parkinson’s disease (PD) [1]
F2-IsoP levels in astrocytes pretreated with oxothiazolidine-4-carboxylic acid (OTC) followed by Mn exposure for 6 hrs were statistically indistinguishable from controls
Environmental exposure to Mn leads to a neurodegenerative illness that has shared pathophysiology and clinical findings with PD
Summary
Environmental exposure to manganese (Mn) leads to manganism, characterized by dopaminergic (DAergic) neurodegeneration, with clinical findings in humans that are reminiscent of idiopathic Parkinson’s disease (PD) [1]. The present study is related to the possible implications of Mn effects in brain cells, as Mn-neurotoxicity may have a role in neurodegenerative processes and disorders of the basal ganglia. Scientific studies addressing a possible role for Mn in PD are timely, as interaction between genetics and environmental factors may lead to PD [7,9]. Dysfunction of the mitochondria is a shared hallmark of both PD and Mn exposure [5,8,17,18], leading some to hypothesize that PD and manganism should be considered as disorders of mitochondrial energy deficiency. Mn leads to alteration in energy and glucose metabolism with ATP depletion and cell death [25,26,27,28,29], concomitant with mitochondrial dysfunction
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