Study On IRP2 Gene In Mice May Help Understand Neurodegenerative Human Disorders

Iron is an essential nutrient for most cells, because iron-containing proteins catalyze many essential reactions of energy metabolism. Iron-overload, however, is detrimental to most organs, and so a cellular mechanism for fine-tuning levels of iron is necessary. Dietary iron is absorbed by epithelial cells lining the intestine, and circulated throughout the rest of the body by a protein called transferrin, to which it binds. Each cell imports varying amounts of transferrin-bound iron, depending on its needs, by tweaking the levels of the transferrin receptor (TfR) at its surface. Once inside of the cell, iron is incorporated into functional enzymes or sequestered by a storage protein called ferritin. To maintain appropriate levels of iron, cells produce two types of iron regulatory proteins (IRPs). One of these, IRP2, shows a greater abundance in the brain than elsewhere. When iron runs low, the IRPs bind to precursor molecules (called messenger RNAs) of TfR and ferritin, resulting in a ramping up of TfR and a diminution of ferritin. This results in higher levels of available iron inside of the cell.

In this issue (Nature Genetics, Vol. 27, Issue 2, 01 Feb 2001), Tracey Rouault and colleagues (of the National Institute of Child Health and Development in Maryland, USA) describe the effect of ablating the gene encoding IRP2 in mice. They observe increased amounts of ferritin and iron in both the intestine and some parts of the brain. The neurons that accumulate iron subsequently degenerate and the mice develop movement disorders, including ataxia and tremor. Excess neuronal iron has been implicated in the pathogenesis of many neurodegenerative human disorders, including Parkinson disease and Freidreich ataxia. The IRP2-deficient mice show neurodegeneration in the same areas as people with multiple system atrophy, indicating that mutations in human IRP2 may be the cause of the disorder. Other neuropathologies show degeneration in only subsets of neurons, but the basis for such selective neuronal vulnerability is unclear. This study indicates that defects in specific components of the iron metabolism system, each possibly produced in varying amounts in different types of neurons, could be part of the explanation.

CONTACT:

Dr. Tracey A. Rouault
Cell Biology and Metabolism Branch
National Institute of Child Health-NIH
Bethesda, Maryland, USA
Telephone: +1 (301) 496 6368
Fax: +1 (301) 402 0078
e-mail: rouault@mail.nih.gov

Dr. Rick Eisenstein
University of Wisconsin
Madison, Wisconsin
Telephone: +1 (608) 262-5830
Fax: +1 (608) 262-5860
e-mail: eisenste@nutrisci.wisc.edu

(C) Nature Genetics press release.

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