Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice

In mammalian cells, regulation of the expression of proteins involved in ir on metabolism is achieved through interactions of iron-sensing proteins kno wn as iron regulatory proteins (IRPs), with transcripts that contain RNA st em-loop structures referred to as iron responsive elements (IREs). Two dist inct but highly homologous proteins, IRP1 and IRP2, bind IREs with high aff inity when cells are depleted of iron, inhibiting translation of some trans cripts, such as ferritin, or turnover of others, such as the transferrin re ceptor (TFRC). IRPs sense cytosolic iron levels and modify expression of pr oteins involved in iron uptake, export and sequestration according to the n eeds of individual cells(1,2). Here we generate mice with a targeted disrup tion of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adul thood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegenerat ion and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of th e brain. Abnormal accumulations of ferritin colocalize with iron accumulati ons in populations of neurons that degenerate, and iron-laden oligodendrocy tes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron m etabolism leads to neurodegenerative disease in Ire62(-/-) mice and may con tribute to the pathogenesis of comparable human neurodegenerative diseases.