Trends in Molecular Medicine
OpinionBrain iron transport and neurodegeneration
Section snippets
Transferrin-bound and non-transferrin-bound iron in the brain
The mechanisms of iron transport across the blood–brain barrier (BBB) have not yet been completely clarified. The accumulated evidence suggests that the transferrin–transferrin receptor (Tf–TfR) pathway might be the major route of iron transport across the luminal membrane of the capillary endothelium 7, 8, 9, and that iron, possibly in the form of Fe2+, crosses the abluminal membrane and enters the interstitial fluid (IF). However, the molecular events of this process are not known 7, 8 (Fig. 1
Initial cause or secondary consequence
Despite considerable investigation, it is still not clear whether excessive iron accumulation in the brain is an initial event that causes neuronal death or is a consequence of the disease process 2, 3. On the basis of current knowledge, however, it seems reasonable to propose that brain iron misregulation is an initial cause of neuron death in some, but not all, NDs. The evidence suggests that the abnormally increased iron levels in the brain could result from disruption in the production of
Conclusion
In this article, we suggest that, at least in some NDs, brain iron misregulation is an initial cause of neuronal death and that this misregulation might be led by either genetic or non-genetic factors. Also, we propose that iron and iron-induced oxidative stress constitute a common mechanism involved in the development of neurodegeneration. However, it should be pointed out that many relevant questions need to be clarified. The precise roles and mechanisms of iron transport proteins in brain
Outstanding questions
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How many types of iron transport proteins are there in the brain, what is their cellular and regional distribution and what is their physiological importance in brain iron homeostasis?
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How is the production of iron transport proteins controlled in the brain under physiological circumstances?
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What are the genetic or non-genetic causes that might lead to misregulation of the production of brain iron transport proteins?
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What is the transport form of iron across the abluminal part of the capillary
Acknowledgments
The studies in this laboratory were supported by Competitive Earmarked Grants from the HK Research Grants Council (A/C: 357/026-B-Q151 and 354/117-B-Q164) and HK Polytechnic University Grants (A/C: A-P136, A-PA79, A-PB48 and G12.xx.93A2).
References (46)
Iron metabolism
Curr. Opin. Chem. Biol.
(1999)- et al.
Expression of iron transport proteins and excessive iron accumulation of iron in the brain in neurodegenerative disorders
Brain Res. Rev.
(1998) Redox metals and neurodegenerative disease
Curr. Opin. Chem. Biol.
(1999)Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells
Biochim. Biophys. Acta
(2000)Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanism
J. Biol. Chem.
(1999)The sky blue protein
J. Lab. Clin. Med.
(1999)Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain
J. Biol. Chem.
(2000)Ceruloplasmin, transferrin and apotransferrin facilitate iron release from human liver cells
FEBS Lett.
(1997)Role of ceruloplasmin and ascorbate in cellular iron release
J. Lab. Clin. Med.
(1999)The Fet3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake
Cell
(1994)
Iron and copper transport in yeast and its relevance to human disease
Trends Biochem. Sci.
Stimulation of the ferroxidase activity of ceruloplasmin during iron loading into ferritin
Arch. Biochem. Biophys.
Pumping iron in the '90s
Trends Cell Biol.
Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin
Brain Res.
Melanotransferrin is produced by senile plaque-associated reactive microglia in Alzheimer's disease
Brain Res.
The G185R mutation disrupts function of iron transporter Nramp2
Blood
Human Nramp2/DMT1, which mediates iron transport across endosomal membrane, is localized to late endosome and lysosomes in Hep-2 cells
J. Biol. Chem.
The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border
Blood
Iron crosses the endosomal membrane by a carrier-mediated process
Prog. Biophys. Mol. Biol.
Regulating the fate of mRNA: the control of cellular iron metabolism
Cell
The copper transport protein Atox1 promotes neuronal survival
J. Biol. Chem.
The role of iron in neurodegeneration
Drugs Aging
Hallervorden–Spatz and brain iron metabolism
Arch. Neurol.
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