Considering all cases and controls studied, 7.4% of MS cases and 1.7% of healthy matched controls were -8GG homozygous for the FPN1 -8GC gene variant with an overall OR-value of 4.9 (95%CI, 1.8-13.3; P=0.001) compared with wild-type -8CC reference genotype. This statistically indicates that the FPN1 -8GG homozygous genotype associated with an increased risk for MS of about five to seven-folds. Considering the patterns related with the course of MS disease, the risk was most evident in SP cases. PP cases fall short of significant result arising form fewer number of cases studied. Association of polymorphism in FPN1 related with MS insights a major role of iron overload and disease prognosis since this protein is expressed in a number of CNS port e.g. oligodendrocytes, neurons, astrocytes, and BBB-cells and plays a major role in extra and intra cellular iron trafficking (3). Till date no extensive studies have been done related with FPN1 gene mutation and its association with disease progression and susceptibility. The polymorphism in FPN1 may play a vital role in CNS physiology in variety of ways either enforcing anti efflux of iron from inside cell creating oxidative stress and cell death or producing molecular defects in FPN-IREs-IRPs machinery since in previous studies, there is mentioned one similar ferritin polymorphism that leads to hereditary hyperferritinemia (4).
In detail, by means a retrospective observational period
of ten years, those RR-patients carrying the -582G-allele had a higher chance to
progress in SP phenotype (log-rank; P=0.019).
It is noteworthy, that the number of -582GG homozygotes
increased considering the most severe MS clinical phenotypes (i.e. RR, 5.5%; SP,
11.0%; PP, 23.3%; P-trend=0.01).
Wu, L.J. et al.
Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier.
Iron homeostasis in the mammalian brain is an important and poorly understood subject. Transferrin-bound iron enters the endothelial cells of the blood-brain barrier from the systemic circulation, and iron subsequently dissociates from transferrin to enter brain parenchyma by an unknown mechanism. In recent years, several iron transporters, including the iron importer DMT1 (Ireg1, MTP, DCT1) and the iron exporter ferroportin (SLC11A3, Ireg, MTP1) have been cloned and characterized. To better understand brain iron homeostasis, we have characterized the distribution of ferroportin, the presumed intestinal iron exporter, and have evaluated its potential role in regulation of iron homeostasis in the central nervous system. We discovered using in situ hybridization and immunohistochemistry that ferroportin is expressed in the endothelial cells of the blood-brain barrier, in neurons, oligodendrocytes, astrocytes, and the choroid plexus and ependymal cells. In addition, we discovered using techniques of immunoelectron microscopy and biochemical purification of synaptic vesicles that ferroportin is associated with synaptic vesicles. In the blood-brain barrier, it is likely that ferroportin serves as a molecular transporter of iron on the abluminal membrane of polarized endothelial cells. The role of ferroportin in synaptic vesicles is unknown, but its presence at that site may prove to be of great importance in neuronal iron toxicity. The widespread representation of ferroportin at sites such as the blood-brain barrier and synaptic vesicles raises the possibility that trafficking of elemental iron may be instrumental in the distribution of iron in the central nervous system.
Altered Iron Metabolism Is Part of the Choroid Plexus Response to Peripheral Inflammation
Iron is essential for normal cellular homeostasis but in excess promotes free radical formation and is detrimental. Therefore, iron metabolism is tightly regulated. Here, we show that mechanisms regulating systemic iron metabolism may also control iron release into the brain at the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. Intraperitoneal administration of lipopolysaccharide (LPS) in mice triggers a transient transcription of the gene encoding for hepcidin, a key regulator of iron homeostasis, in the choroid plexus, which correlated with increased detection of pro-hepcidin in the CSF. Similarly, the expression of several other iron-related genes is influenced in the choroid plexus by the inflammatory stimulus. Using primary cultures of rat choroid plexus epithelial cells, we show that this response is triggered not only directly by LPS but also by molecules whose expression increases in the blood in response to inflammation, such as IL-6. Intracellular conveyors of these signaling molecules include signal transducer and activator of transcription 3, which becomes phosphorylated, and SMAD family member 4, whose mRNA levels increase soon after LPS administration. This novel role for the choroid plexus-CSF barrier in regulating iron metabolism may be particularly relevant to restrict iron availability for microorganism growth, and in neurodegenerative diseases in which an inflammatory underlying component has been reported.
The Journal of Neuroscience, 14 September 2011, 31(37): 13301-13311; doi: 10.1523/JNEUROSCI.2838-11.2011
Iron Efflux from Oligodendrocytes Is Differentially Regulated in Gray and White MatterKatrin Schulz1, Chris D. Vulpe2, Leah Z. Harris3, and Samuel David1
+ Author Affiliations
1Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec H3G 1A4, Canada,
2Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, and
3Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232
Author contributions: K.S. and S.D. designed research; K.S. performed research; C.D.V. and L.Z.H. contributed unpublished reagents/analytic tools; K.S. and S.D. analyzed data; K.S. and S.D. wrote the paper.
Accumulation of iron occurs in the CNS in several neurodegenerative diseases. Iron is essential for life but also has the ability to generate toxic free radicals if not properly handled. Iron homeostasis at the cellular level is therefore important to maintain proper cellular function, and its dysregulation can contribute to neurodegenerative diseases. Iron export, a key mechanism to maintain proper levels in cells, occurs via ferroportin, a ubiquitously expressed transmembrane protein that partners with a ferroxidase. A membrane-bound form of the ferroxidase ceruloplasmin is expressed by astrocytes in the CNS and regulates iron efflux. We now show that oligodendrocytes use another ferroxidase, called hephaestin, which was first identified in enterocytes in the gut. Mice with mutations in the hephaestin gene (sex-linked anemia mice) show iron accumulation in oligodendrocytes in the gray matter, but not in the white matter, and exhibit motor deficits. This was accompanied by a marked reduction in the levels of the paranodal proteins contactin-associated protein 1 (Caspr) and reticulon-4 (Nogo A). We show that the sparing of iron accumulation in white matter oligodendrocytes in sex-linked anemia mice is due to compensatory upregulation of ceruloplasmin in these cells. This was further confirmed in ceruloplasmin/hephaestin double-mutant mice, which show iron accumulation in both gray and white matter oligodendrocytes. These data indicate that gray and white matter oligodendrocytes can use different iron efflux mechanisms to maintain iron homeostasis. Dysregulation of such efflux mechanisms leads to iron accumulation in the CNS.
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