Short reviewExpression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders
Introduction
Abnormally high levels of iron and oxidative stress have been demonstrated in a number of neurodegenerative disorders 17, 18, 37, 52, 78, 82, 84, 92. The increased level of brain tissue iron has been implicated as a major generator of reactive oxygen species which are capable of damaging biological molecules such as lipids, carbohydrates, proteins, and nucleic acids 77, 93. Oxidative stress resulting from the increased iron levels, and possibly also from defects in antioxidant defense mechanisms, is widely believed to be one of causes responsible for neuronal death in neurodegenerative diseases 11, 24, 36, 38, 47, 73, 79, 94, although there is still no general agreement as to the causative link between iron-induced oxidative stress and the neuronal death. However, brain cells need iron. Iron is the most abundant trace metal in the brain 5, 6. The concentration of iron in the brain is region dependent, and in the basal ganglia iron is present at a concentration equal to that found in the liver. At the cell level, the oligodendrocyte is the predominant cell type containing iron in the brain 7, 16. The importance of iron for normal neurological function has been well established. As in all cells, neurons and glia require iron for many aspects of their physiology, including electron transport, NADPH reductase activity, myelination of axons, and as a co-factor for several enzymes involved in neurotransmitter synthesis. Hence, an imbalance in brain iron results in dysfunction in iron related metabolism 8, 35, 71, 83. To date, however, very little is known about the regulation of iron concentration in the central nervous system and mechanisms of iron uptake by and release from brain cells. It is for this reason that we are not yet able to answer this important question: why do iron levels increase abnormally in some regions of the brain in neurodegenerative disorders?
The regulation and management of iron at the cellular level is primarily by two proteins found in most cells throughout the body: transferrin receptor (TfR) and ferritin (Ft). By controlling the level of expression of these two proteins, the cell can determine the amount of iron acquired (proportional to the number of membrane TfR) and sequestered (proportional to the cytoplasmic level of Ft). In most types of cells, the coordinated control of TfR and Ft by cellular iron occurs at the post-transcriptional level and is mediated by cytoplasmic RNA binding proteins, known as the iron regulatory proteins (IRPs) 10, 44. The same elegant system that exists in extraneural organs has been demonstrated in brain cells for regulating iron concentration and availability [48]. Based on the accumulated information, however, it is highly likely that TfR expression is not the only factor determining iron uptake by brain cells, nor is transferrin (Tf) the only transporter of iron in the brain. This possibility is supported by the following findings: (1) Photomicrographs of brain sections stained for iron show that there is little overlap in the distribution of TfR and iron. Except for the interpeduncular nucleus, no other iron-rich area of the brain has an abundance of TfR and the areas with dense TfR have little or no stainable iron 29, 45. (2) Quantitative measurements of the entry and exit rates of iron and Tf in mice have demonstrated that the blood to brain transport of iron is greater than that of Tf while the brain to blood transport of Tf is greater than that of iron. These differences between the transport rates of iron and Tf suggest that at least some iron transport across the blood brain barrier (BBB) does not depend on Tf and its receptor [4]. (3) Cerebrospinal fluid (CSF) iron concentration exceeds the iron-binding capacity of Tf present in CSF, thus, other proteins and molecules may bind and transport iron in the brain 5, 9; (4) Hypotransferrinemic mice have been shown to have higher than normal iron uptake into the brain and a significant amount of iron is transported into brain by a route independent of Tf/TfR [88]. (5) The localization of Tf in the brain does not coincide with its receptor 29, 46. (6) Non transferrin-bound iron can cross the BBB although a major portion of iron transport across BBB is normally Tf-mediated [88]. Therefore, it seems reasonable to believe that the mechanisms of iron uptake by and release from brain cells and homeostatic control of iron in the brain are, at least in part, different from those in tissues and cells outside of the brain. There may be some other proteins or molecules involved in brain iron metabolism in addition to Tf and TfR. Recent studies on lactotransferrin receptor (LfR), melanotransferrin (MTf), ceruloplasmin (CP) and divalent cation transporter (DCT1) provide strong evidence to support this viewpoint. These recent findings have greatly improved our knowledge of iron transport in the brain. This short review will focus on the recent advances in studies on these four proteins, placing emphasis on their possible role in physiological iron transport in the brain and the hypothetical connection of their disrupted expression with excessive accumulation of brain iron in neurodegenerative diseases. The updated understanding of the role of Tf/TfR pathway and Ft in brain iron balance and the association of TfR and Ft dysregulation with brain iron imbalance in neurodegenerative diseases have recently been well-reviewed elsewhere 5, 6, 12, 21, 23, 35, 36, 93.
Section snippets
Lactotransferrin receptor
Lactotransferrin receptor (also called lactoferrin receptor), a monomeric glycoprotein of 105 kDa which was previously identified only in monocytes and intestinal cells [49], has been demonstrated to express in the brain. The overproduction of this protein has been linked with increased intraneuronal iron levels and degeneration of nigral dopaminergic neurons in PD 11, 32, 64.
The well-established process of iron uptake in mammalian cells is mainly mediated by the Tf/TfR pathway 72, 74. Hence,
Melanotransferrin
Melanotransferrin (MTf), an iron binding protein recently identified in the brain tissue, may play a physiological role in iron transport within the human brain. The overexpression of this protein may be involved in excess iron accumulation in the brain and hence associated with the development of Alzheimer's disease 50, 51, 58, 59, 81.
The melanotransferrin molecule, also called p97 (human melanoma tumor-associated antigen), was first identified on the surface of melanoma cells [13]. This
Ceruloplasmin
Ceruloplasmin, a blue copper-containing oxidase that is mainly synthesized in hepatocytes, is also synthesized in the central nervous system and is probably involved in brain iron metabolism. The decreased or absent expression of this protein may induce excessive iron accumulation in brain cells in aceruloplasminemia and perhaps in a variety of neurodegenerative diseases where abnormalities in iron metabolism have been demonstrated 20, 42, 54, 61, 62.
Ceruloplasmin is an abundant serum α2
Divalent cation transporter
Divalent cation transporter (DCT1) is a new mammalian proton-coupled metal-ion transport protein. Its presence in the brain and other tissues has recently been reported by Gunshin et al. [40]. The possible role of DCT1 in physiological iron transport in the brain has been suggested and the defects in this membrane protein has been associated with brain iron imbalance and neuronal death in neurodegenerative diseases [40].
This integral membrane protein consists of 561 amino-acids with 12 putative
Conclusion and perspectives
How iron homeostasis in the brain is maintained is an area of increasing interest in neurobiology. The full understanding of homeostatic mechanisms involved in brain iron metabolism is fundamental and critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions that can disrupt the chain of pathological events occurring in neurodegenerative diseases caused by iron accumulation.
Acknowledgements
The research in this laboratory was supported by Competitive Earmarked Grants of The Hong Kong Research Grants Council (A/C 357/026 and 354/117) and The Hong Kong Polytechnic University Research Grants (A/C 353/105, 350/314, 350/814, 350/664 and 350/539). We are grateful to Professor E.H. Morgan, Department of Physiology, The University of Western Australia, Australia and Professor P.L. Tang, The Hong Kong Polytechnic University for their helpful suggestions, comments and English revision.
References (95)
- et al.
Transferrin: insights into structure and function from studies on lactoferrin
Trends Biochem. Sci.
(1987) - et al.
Human melanotransferrin (p97) has only one functional iron-binding site
FEBS Lett.
(1992) - et al.
Studies of the slow bidirectional transport of iron and transferrin across the blood-brain barrier
Brain Res. Bull.
(1988) - et al.
Are reactive oxygen species involved in Alzheimer's disease?
Neurobiol. Aging
(1995) - et al.
The determination of non-heme iron and transferrin in cerebrospinal fluid
Clin. Chim. Acta
(1971) - et al.
An update on iron metabolism: summary of the fifth international conference on disorders on iron metabolism
Hepatology
(1996) Pumping iron in Parkinson's disease
Lancet
(1996)- et al.
Ceruloplasmin levels in the human superior temporal gyrus in aging and Alzheimer's disease
Neurosci. Lett.
(1993) - et al.
Nonidentical distribution of transferrin and ferric iron in Human brain
Neuroscience
(1988) - et al.
Autoradiographic localization and density of [] ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson's disease and MPTP-lesioned monkeys
Brain Res.
(1995)
The density of -transferrin binding sites on perikarya of melanized neurons of the substantia is decreased in Parkinson's disease
Brain Res.
Transport and expression in human melanomas of a transferrin-like glycosylphosphatidylinositol-anchored protein
J. Biol. Chem.
Oxidative stress: free radical production in neural degeneration
Pharmacol. Ther.
The regional distribution and cellular localization of iron in the rat brain
Neuroscience
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.
Oxidative damage in neurodegenerative disease
Lancet
Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease
Brain Res.
Regulating the fate of mRNA: the control of cellular iron metabolism
Cell
The iron binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis
Brain Res.
Increased regional brain concentration of ceruloplasmin in neurodegenerative disorders
Brain Res.
Mechanisms of iron uptake by mammalian cells
Biochim. Biophys. Acta
Iron crosses the endosomal membrane by a carrier-mediated process
Prog. Biophys. Mol. Biol.
Coincident expression and distribution of melanotransferrin and transferrin receptor in human brain capillary endothelium
Brain Res.
Astrocytes, brain aging, and neurodegeneration
Neurobiol. Aging
The role of iron in beta amyloid toxicity
Biochem. Biophys. Res. Commun.
Developmental changes in transferrin and iron uptake by the brain in the rats
Dev. Brain Res.
Glycosyl phosphatidylinositol membrane anchoring of melanotransferrin (p97): apical compartmentalization in intestinal epithelial cells
J. Cell. Sci.
Iron in the brain
Nutr. Rev.
Brain iron: location and function
Prog. Food. Nutr. Sci.
Ferrit, transferrin and iron in normal and aged rat brains
Anat. Rec.
Transport of iron in the blood-brain–cerebrospinal fluid system
J. Neurochem.
Structural characterization of human melanoma-associated antigen p97 with monoclonal antibodies
J. Immunol.
Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation
Science
Nramp defines a family of membrane proteins
Proc. Natl. Acad. Sci. USA
Cellular distribution of transferrin, ferritin and iron in normal and aged human brains
J. Neurosci. Res.
A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brain
J. Neurosci. Res.
The regional distribution of iron and iron regulatory proteins in the brain in aging and Alzheimer's disease
J. Neurosci. Res.
Iron regulation in the brain at the cell and molecular level
Adv. Exp. Med. Biol.
A quantitative analysis of isoferritins in selectregions of aged, parkinsonian, and Alzheimer's diseased brains
J. Neurochem.
Relationship of iron to oligodendrocytes and myelination
Glia
Free radicals and neuronal cell death
Cell Death Differ.
Molecular mechanisms of iron uptake in eukaryotes
Physiol. Rev.
Decreased ferritin levels in Parkinson's disease
J. Neurochem.
Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia
Ann. Neurol.
Cellular distribution of iron, transferrin, and ferritin in the hypotransferremic (Hp) mouse brain
J. Comp. Neurol.
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