Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Abstract

Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mismetabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324Signal. 20, -1363

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

“…These cells express relatively low levels of endogenous PrP C and thus provide a useful model for the evaluation of exogenously expressed human PrP C and its FR-deficient mutant PrP ⌬51-89 in iron uptake and transport (5). 4 Here, we report that PrP C promotes the uptake and transport of NTBI and Tf-iron from the glomerular filtrate in vivo and mainly NTBI across PT cells in vitro through its FR activity. However, excess NTBI and hemin aggregate PrP C to a detergent-insoluble form, preventing further iron uptake.…”

“…Major known FR proteins in these cells include duodenal cytochrome b on the AP plasma membrane and Steap3 in the membrane of acidic endosomes (12,13). Iron transported to the cytosol is utilized for metabolic purposes, oxidized by ferritin, and stored in its shell or exported from the BL membrane by the coupled action of ferroportin and hephaestin, a ferroxidase that oxidizes exported Fe 2ϩ to Fe 3ϩ for conjugation with circulating apoTf to form diferric-Tf (Tf-iron) (4,14). Second, expression of PrP C has been described in the kidney (15,16), and significant amounts of full-length, truncated, and various glycosylated forms of PrP C are present in the urine of healthy individuals (17)(18)(19).…”

“…It is remarkable that the majority of PrP C in the urine is similar to the anchorless, N-terminally processed form observed in human and animal brains and neuronal cell models, suggesting similar processing of PrP C by kidney epithelial and cortical neuronal cells (20 -22). More importantly, the presence of PrP C in the urine of healthy individuals suggests that it is expressed on PT cells where it may provide FR activity necessary for the uptake of Tf-iron and NTBI (4,5,17).…”

“…The physiological function of PrP C or the mechanism of neurotoxicity by PrP Sc , however, remains unclear. Cumulative evidence indicates brain iron dyshomeostasis as a prominent feature of human and animal prion disorders, implicating redox-active iron in disease-associated neurotoxicity (3,4). The underlying cause of iron dyshomeostasis is not clear, although recent reports suggest loss or altered function of PrP C in cellular iron uptake via its ferrireductase (FR) activity as a possible cause (5).…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The ferritin isolated form affected brains is insoluble and retains iron even when exposed to harsh denaturing conditions. These aggregates can exert a pro-oxidant activity and favor further accumulation of PrPsc and, in the long run, may lead to an iron-deficient phenotype with upregulation of TfR expression (Singh et al 2014). Altogether these observation suggest that different factors (mutations, altered subunits ratio, interaction with other protein/molecules) may affect the ferritin capacity to properly modulate the dynamic sequestration and release of iron and induce a switch towards a pro-oxidant activity of the protein, possibly contributing to the development and/or progression of some neurodegenerative processes (figure 6).…”