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