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Letter to the Editor

Limited Role of Transferrin in Manganese Transport to the Brain

Department of Neuroscience & Anatomy, Penn State College of Medicine, Hershey, PA 17033

Dear Editor:

In The Journal of Nutrition, Kwik-Uribe et al. (1) described changes in myelin and neurotransmitters in rats subjected to iron deficiency. These observations underscore the importance of nutrition in early brain development. The authors also observed increased brain Mn concentrations in the iron-deficient rats, which were interpreted to be the result of brain uptake of manganese (Mn) via the transferrin (Tf)/transferrin receptor (TfR) system.

The observed inverse relationship between brain Mn concentrations and iron status is not new (2) . To ascribe this effect solely to the Tf/TfR mechanism is unwarranted if the supporting references are examined carefully and recent developments in the field are considered.

The Tf/Mn hypothesis seemed a logical one because Mn²⁺ can be oxidized to Mn³⁺ and bind to Tf (3) ; this Mn-Tf complex can be internalized by neuroblastoma cells (4) . However, the oxidation is slow in plasma (5) , and neuroblastoma cells are not a good model for transport of substances into neurons. First, tumor cell lines have more Tf receptors than primary cells, and second, transport of substances into the brain requires translocation across either the blood-brain barrier or the choroid plexus-cerebrospinal fluid (CSF) system (6) .

More recent experiments expose flaws in the Mn/Tf hypothesis. Rabin et al. (7) and Aschner and Gannon (8) found that coadministration of Mn²⁺ with plasma or Tf either lowered or did not change total brain Mn uptake. The study by Takeda et al. (9) confirmed that coadministration of Mn²⁺ with Tf decreased total brain uptake of Mn, and further showed that this resulted in no significant changes in its pattern of accumulation. The direct test of the Mn/Tf hypothesis was performed in our laboratory using the hypotransferrinemic mouse (hpx/hpx; 10 ). In the case of Fe³⁺, hpx/hpx mice were able to transport Fe³⁺ only into the choroid plexus (where the blood-brain barrier is replaced by fenestrated capillaries, stroma, and an epitheilal cell layer which secretes CSF), whereas wild-type controls exhibited widespread brain Fe³⁺ uptake (Tf receptors are numerous on capillaries comprising the blood-brain barrier). The Mn²⁺ uptake in the hpx/hpx mice was essentially normal, clearly showing that some other transporter system accounts for brain Mn uptake.

In light of these recent experiments showing a limited role of Tf in Mn transport, the question remains concerning the mechanism(s) for Mn transport into the brain. The iron transporter DMT-1 also transports Mn²⁺, and this transporter has been localized in the brain. There remains the possibility of the existence of Mn transporters as yet undiscovered. Thus, readers of this journal should not be misled by the interpretation of Kwik-Uribe et al. (1) that Tf is the predominant mechanism for transport of Mn to the brain.

REFERENCES

1. Kwik-Uribe C. L., Gietzen D., German J. B., Golub M. S., Keen C. L. Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J. Nutr. 2000;130:2821-2830[Abstract/Free Full Text]

2. Malecki E. A., Devenyi A. G., Barron T. F., Mosher T. J., Eslinger P. J., Flaherty-Craig C. V., Rossaro L. Iron and manganese homeostasis in chronic liver disease: relationship to pallidal T1-weighted magnetic resonance signal hyperintensity. Neurotoxicology 1999;20:647-652[Medline]

3. Scheuhammer A. M., Cherian M. G. Binding of manganese in human and rat plasma. Biochim. Biophys. Acta 1985;840:163-169[Medline]

4. Suárez N., Erikson H. Receptor-mediated endocytosis of a manganese complex of transferrin into neuroblastoma (SHSY5Y) cells in culture. J. Neurochem. 1993;61:127-131[Medline]

5. Critchfield J. W., Keen C. L. Manganese+2 exhibits dynamic binding to multiple ligands in human plasma. Metabolism 1992;41:1087-1092[Medline]

6. Malecki E. A., Devenyi A. G., Beard J. L., Connor J. R. Existing and emerging mechanisms for iron and manganese transport to the brain. J. Neurosci. Res. 1999;56:113-122[Medline]

7. Rabin O., Hegedus L., Bourre J.-M., Smith Q. R. Rapid uptake of manganese (II) across the blood-brain barrier. J. Neurochem. 1993;61:509-517[Medline]

8. Aschner M., Gannon M. Manganese transport across the blood-brain barrier: saturable and transferrin-dependent transport mechanisms. Brain Res. Bull. 1993;33:345-349

9. Takeda A., Ishiwatari S., Okada S. Influence of transferrin on manganese uptake in rat brain. J. Neurosci. Res. 2000;59:542-552[Medline]

10. Malecki E. A., Cook B. M., Devenyi A. G., Beard J. L., Connor J. R. Transferrin is required for normal distribution of ⁵⁹Fe and ⁵⁴Mn in brains of mice. J. Neurol. Sci. 1999;170:112-118[Medline]

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