The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain

Abstract

Brain iron transport and distributional pattern of divalent metal transporter I (DMT1) were studied in homozygous Belgrade rats (b/b) which suffer from a mutation in the DMT1 gene. In adult rats, brain uptake of transferrin-bound iron injected intravenously (i.v.) was significantly lower compared with that in heterozygous Belgrade (+/b) and Wistar rats, whereas transferrin uptake was identical. The difference in iron uptake was not apparent until 30 min after injection. The brain iron concentration was lower, and neuronal transferrin receptorimmunoreactivity higher, in adult b/b rats, thus confirming their iron-deficient stage. Antibodies targeting different sites on the DMT1 molecule consistently detected DMT1 in neurones and choroid plexus at the same level irrespective of strain, but failed to detect DMT1 in brain capillary endothelial cells (BCECs), or macro-or microglial cells. The absence of DMT1 in BCECs was confirmed in immunoblots of purified BCECs. DMT1 was virtually undetectable in neurones of rats aged 18 post-natal days irrespective of strain. Neuronal expression of transferrin receptors and DMT1 in adult rats implies that neurones at this age acquire iron by receptor-mediated endocytosis of transferrin followed by iron transport out of endosomes mediated by DMT1. The existence of the mutated DMT1 molecule in neurones suggests that the low cerebral iron uptake in b/b rats derives from a reduced neuronal uptake rather than an impaired iron transport through the blood-brain barrier. Keywords: blood-brain barrier, choroid plexus, endocytosis, ferric reductase, human autopsies, transferrin receptor. Abbreviations used: AUC, the area under the plasma radioactivity curve; +/b, heterozygous Belgrade rat; b/b, homozygous Belgrade rat; BBB, blood-brain barrier; BCEC, brain capillary endothelial cell; BSA, bovine serum albumin; DMT1, divalent metal transporter I; Fe, iron; IRE, iron responsive element; IRP, iron regulatory protein; KPBS, potassium phosphate-buffered saline; P, postnatal; Vd, volume of distribution.

Upregulation of DMT1 expression in choroidal epithelia of the blood–CSF barrier following manganese exposure in vitro

“…For example, animal models with DMT1 mutation, such as mk mice and Belgrade rats, have shown the defects in iron transport function, leading to anemia Fleming et al, 1997;Gruenheid et al, 1999;Su et al, 1998). Studies on brain barriers have also suggested that iron can be transported across the BBB and BCB into the CNS through a non-Tfmediated transport (Bradbury, 1997;Moos and Morgan, 2004;Takeda et al, 2002). A recent study from this laboratory by using brain perfusion technique demonstrates that nontransferrin-bound iron can get access to the CSF en route the choroid plexus by a yet unidentified mechanism (Deane et al, 2004).…”

“…The presence of DMT1 in the choroid plexus, the tissue where the blood-CSF barrier is located, has been demonstrated in the tissues from rats, mice and humans (Choudhuri et al, 2003;Gunshin et al, 1997;Kishi and Tabuchi, 1997;Knutson et al, 2004;Miller, 2004;Moos and Morgan, 2004;Siddappa et al, 2002). Z310 cells were immortalized cells directly derived from rat choroidal epithelia (Zheng and Zhao, 2002).…”

Iron, Aging, and Neurodegeneration

“…The main storage protein for iron is ferritin, which is composed of a mixture of H-or L-ferritin monomers (heavy or light chain), and varies between cell types as to which is expressed predominantly. Neurons express predominantly H-ferritin while microglia express L-ferritin [19,20]. Some neurons, such as those of the substantia nigra, express neuromelanin.…”

Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease

“…These rodents exhibit a significant alteration in the kinetics of brain iron incorporation (28). Nevertheless, although a decrease in Perls iron histochemistry has been reported in the brain of Belgrade rats (29), quantitative techniques detect only mild or nonsignificant decreases in brain iron content in Belgrade rats and mk/mk mice, respectively (ref.…”