Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease

Abstract

Increasing evidence has confirmed that nigral iron accumulation and activation of NMDA receptors (NRs) contribute to the neurodegeneration of dopamine (DA) neurons in Parkinson's disease (PD). Earlier work indicated that activation of NRs participated in iron metabolism in the hippocampus. However, the relationship between activation of NRs and iron accumulation in DA neurons of the substantia nigra in PD was unknown. In this study, our results showed that NRs inhibitors MK-801 and AP5 protected nigrostriatal projection system and reduced nigral iron levels of 6-hydroxydopamine (6-OHDA)-induced PD rats. In vitro studies demonstrated that NMDA treatment increased the expression of iron importer divalent metal transporter 1 (DMT1) and decreased the expression of iron exporter ferropotin 1 (Fpn1), which were dependent on iron regulatory protein 1 (IRP1). This led to increased intracellular iron levels and intensified the decrease in mitochondrial transmembrane potential in MES23.5 dopaminergic neurons. In addition, we reported that MK801 and neuronal nitric oxide synthase inhibitor could antagonize 6-OHDA-induced up-regulation of IRP1 and DMT1 and down-regulation of Fpn1, thus attenuating 6-OHDA-induced iron accumulation in MES23.5 cells. This suggested that 6-OHDA-induced activation of NRs might modulate the expression of DMT1 and Fpn1 via the neuronal nitric oxide synthase-IRP1 pathway.-Xu, H., Liu, X., Xia, J., Yu, T., Qu, Y., Jiang, H., Xie, J., Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease.

Brain iron transport

“…The reduced expression of Fpn1 has also been connected with the activation of N ‐methyl‐D‐aspartate (NMDA) receptor (NR)‐induced iron accumulation and neurodegeneration in dopamine (DA) neurons in Parkinson's disease (Xu et al, ) and brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease (Puy et al, ). Global Heph knockout (Heph KO) has been demonstrated to induce a significant increase in iron levels in the cortex, hippocampus, brain stem and cerebellum in the brain of mice (Jiang et al, ).…”

Iron accumulation typifies renal cell carcinoma tumorigenesis but abates with pathological progression, sarcomatoid dedifferentiation, and metastasis

“…However, these mechanisms alone would not explain tumorigenic specificity for kidney tissue (39)(40)(41)(42)(45)(46)(47). In that regard, we and others have observed that master proteins for cellular free iron elevation (TfR1, DMT1/ SLC11A2, and IRP1/ACO1) collectively have highest body levels in renal tubule epithelium (28)(29)(30), perhaps making this tissue prone to iron accumulation and oxidative stress injury (91). In rodents, repeated high dosing of iron chelated to nitrilotriacetic acid (FeNTA model) effectively targets iron deposition to the renal epithelium, which induces RCC tumorigenesis with high frequency (40-42, 92).…”

Alpha-Lipoic Acid Mediates Clearance of Iron Accumulation by Regulating Iron Metabolism in a Parkinson’s Disease Model Induced by 6-OHDA

“…6-hydroxydopamine, a neurotoxin that can cause degeneration of DA neurons in animal models and cell apoptosis in PC12 cells, has been widely used in PD models ( Glajch et al, 2012 ; Xu et al, 2001 ). Recently, increasing evidence suggested that 6-OHDA may selectively cause the death of nigral neurons or dopaminergic neurons by inducing high levels of iron and oxidative stress ( Lee et al, 2018 ; Xu et al, 2018 ). Thus, inhibiting the elevated iron and oxidative stress induced by 6-OHDA is a potential strategy for protecting neurons.…”