| Literature DB >> 30833886 |
Chao Liu1,2,3,4, Mui Cheng Liang1,4, Tuck Wah Soong1,4,5.
Abstract
Iron is a crucial cofactor for several physiological functions in the brain including transport of oxygen, DNA synthesis, mitochondrial respiration, synthesis of myelin, and neurotransmitter metabolism. If iron concentration exceeds the capacity of cellular sequestration, excessive labile iron will be harmful by generating oxidative stress that leads to cell death. In patients suffering from Parkinson disease, the total amount of iron in the substantia nigra was reported to increase with disease severity. High concentrations of iron were also found in the amyloid plaques and neurofibrillary tangles of human Alzheimer disease brains. Besides iron, nitric oxide (NO) produced in high concentration has been associated with neurodegeneration. NO is produced as a co-product when the enzyme NO synthase converts L-arginine to citrulline, and NO has a role to support normal physiological functions. When NO is produced in a high concentration under pathological conditions such as inflammation, aberrantly S-nitrosylated proteins can initiate neurodegeneration. Interestingly, NO is closely related with iron homeostasis. Firstly, it regulates iron-related gene expression through a system involving iron regulatory protein and its cognate iron responsive element (IRP-IRE). Secondly, it modified the function of iron-related protein directly via S-nitrosylation. In this review, we examine the recent advances about the potential role of dysregulated iron homeostasis in neurodegeneration, with an emphasis on AD and PD, and we discuss iron chelation as a potential therapy. This review also highlights the changes in iron homeostasis caused by NO. An understanding of these mechanisms will help us formulate strategies to reverse or ameliorate iron-related neurodegeneration in diseases such as AD and PD.Entities:
Keywords: Parkinson’s disease; S-nitrosylated proteins; iron homeostasis; nitric oxide; oxidative stress
Year: 2019 PMID: 30833886 PMCID: PMC6388708 DOI: 10.3389/fnins.2019.00114
Source DB: PubMed Journal: Front Neurosci ISSN: 1662-453X Impact factor: 4.677
FIGURE 1Iron homeostasis in the brain. The iron was uptake from blood through brain capillary epithelial cells. Neurons express TfR, DMT1 and Fpn; absorb iron from brain interstitium and export excess iron. Astrocytes form intimate contact with brain capillary epithelial cells through end-feet and may influence iron transport between blood and brain. Astrocytes express TfR1, DMT1 and ZIP-14; and efflux iron via Fpn partnered with ceruloplasmin (Cp). Astrocytes may also efflux iron via endothelial cells into blood. Microglia can acquire iron via TfR1, DMT1 from brain intermedium. Microglia are unable to efflux iron as Fpn is internalized from the cell surface. In aged or neurodegenerative brain, microbleeds may occur. Hemoglobin is released after haemolysis. Haptoglobin binds with hemoglobin form a tight complex. The Hb:Hp complex is bound with the receptor CD163 and undergo endocytosis. The complex are degraded after endocytosis and the iron is absorbed into intracellular iron pool and stored in ferritin. The iron flow direction is indicated by black arrows.
FIGURE 2Schematic chart showing how NO regulate iron homeostasis. NO regulates IRP-IRE binding through redox reaction with Fe–S cluster in IRP, hence regulates the transcription of iron-metabolism-related proteins, and elevates intracellular iron level. NO also directly S-nitrosylates DMT1, which enhances DMT1 transporter function. In addition, NO S-nitrosylates Dexras 1 and enhances the binding of Das1-PAP7-DMT1 complex and finally enhances iron uptake.
FIGURE 3The regulation of NO on iron homeostasis in the brain during neuroinflammation. Large amount of NO was produced by microglia and astrocytes upon activation of iNOS during neuroinflammation. NO enhanced the translation of TfR and DMT1 and decreased the translation of Fpn, hence increased iron accumulation in neurons. The iron accumulation leads to oxidative stress and finally caused neurodegeneration.