26 February 2001. Deleting a critical gene for iron metabolism leads to
selective neurodegeneration, according to a study in this month's Nature
Genetics. When researchers, led by Tracey Rouault and Timothy La Vaute
of the U.S. National Institute of Child Health and Human Development,
ablated the gene for iron regulatory protein 2 (IRP2), they produced
mice that developed progressive movement disorders such as ataxia and
The IRPs (1 and 2) are instrumental in regulating intracellular iron
levels. Cells are initially supplied with iron by the protein
transferrin, which binds iron in the intestine and circulates it
throughout the body. The IRPs respond to fluctuations in intracellular
iron by adjusting the levels of transferrin receptor, as well as the
protein ferritin, which sequesters iron inside cells. A noteworthy
feature of IRP2 is that is particularly abundant in the brain.
In this study, mice completely lacking IRP2 accumulated excess ferritin
and iron in the brain, particularly in cerebellar white matter and areas
such as caudate-putamen, thalamus, and the colliculi. The excess iron
was found in the cytosol of neurons, as well as in oligodendrocytes. The
accumulation of iron was a reliable predictor of subsequent
neurodegeneration in these brain areas. Mice lacking both genes for IRP2
initially developed normally, but after six months of age exhibited a
progressive disease characterized by gait problems, followed by signs
such as ataxia, tremor, and postural abnormalities. In mice lacking only
one gene, the same disorder developed later in life.
Because the link between iron levels and neurodegenerative disease was
so compelling in this animal model, the authors suggest that the
selective neuronal vulnerability seen in many human neurodegenerative
diseases may, in some cases, involve misregulation of iron metabolism.-Hakon Heimer.
Reference:LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, Drake SK, Miller G, Abu-Asab M, Tsokos M, Switzer R 3rd, Grinberg A, Love P, Tresser N, Rouault TA. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice.
Nature Genetics 2001 February;27:209-214. Abstract