Brain iron metabolism and its perturbation in neurological diseases
Enormous advances have been made in the last decade in understanding iron metabolism and iron homeostasis at both the cellular and the systemic level. This includes the identification of genes and proteins involved in iron transport, such as the ferric re
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Abstract
Enormous advances have been made in the last decade in understanding iron metabolism and iron homeostasis at both the cellular and the systemic level. This includes the identification of genes and proteins involved in iron transport, such as the ferric reductase DcytB, the proton-coupled ferrous (divalent) iron transporter DMT1, the iron exporter ferroportin and the membrane-bound ferroxidase hephaestin. The modulation of their translation by the iron regulatory protein (IRP) system has also been identified together with the impressive signalling cascades involved in regulating the chef d’orchestre of systemic iron homeostasis, hepcidin. However, exactly how the brain regulates fluxes and storage of iron between neurons, oligodendrocytes, astrocytes and microglial cells remains an enigma. In this review we discuss the possible mechanisms which may be involved in the transfer of iron across the blood–brain barrier(BBB), together with the possible role played by astrocytes. The consequences of iron deficiency and iron excess on brain function are described. Finally, various neurodegenerative diseases, where accumulation of iron may be important in the pathogenesis, are presented as well as the possible use of iron chelators to diminish disease progression. Keywords
Iron Neurodegeneration Parkinson’s disease Alzheimer’s disease
Introduction Iron (Fe) is a necessary cofactor in many metabolic processes in the central nervous system (CNS), including oxidative phosphorylation, myelin synthesis, neurotransmitter production, nitric oxide metabolism and oxygen transport. It plays an important role in electron transfer and is a cofactor for a large number of enzymes [1], including a number of key enzymes of neurotransmitter biosynthesis in brain, e.g. tyrosine hydroxylase (involved in the synthesis of catecholamines, including dopamine), tryptophan hydroxylase (involved in the synthesis
R.R. Crichton (*) Institute of Condensed Material and Nanosciences, Universite´ Catholique de Louvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium e-mail: [email protected] W. Linert and H. Kozlowski (eds.), Metal Ions in Neurological Systems, DOI 10.1007/978-3-7091-1001-0_1, # Springer-Verlag Wien 2012
of serotonin) and monoamine oxidase (involved in the metabolism of dopamine). It is essential that iron fluxes and storage within the brain are controlled within very exact limits in order to have adequate supplies for such metabolic processes but not ‘too much’, which could exacerbate damage via Fenton chemistry.
A brief overview of iron metabolism and homeostasis Iron is transported throughout the circulation bound to the iron transport protein transferrin (Tf), which binds two atoms of Fe3+ as diferric transferrin Fe3þ 2 Tf . Such iron is delivered to cells via the transferrin-to-cell cycle (Fig. 1) and binds to its receptor, and the complex is invaginated into clathrin-coated pits, which fuse with the target membranes 1
2
R.R. Crichton et al. Clathrincoated pit
DMT1
HOLO-TF
APO-TF TFR
Fe2+
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