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

Abstract

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, 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 neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.

Human iron regulatory protein 2 is easily cleaved in its specific domain: consequences for the haem binding properties of the protein

“…Inactivation of both IRP1 and IRP2 is lethal at an early stage during embryonic development [9]. The disruption of IRP2 has also been associated with brain iron overload and the development of a neurodegenerative movement disorder [6,9]. However, other IRP2 −/− mice do not show obvious signs of neurodegeneration [10].…”

“…IRP2 −/− mice develop microcytic anaemia [6][7][8], whereas IRP1 −/− mice are asymptomatic. Inactivation of both IRP1 and IRP2 is lethal at an early stage during embryonic development [9].…”

Nitric oxide, oxidants, and protein tyrosine nitration

“…The hemeperoxidaseindependent nitration observed in MPO and EPO knockouts (15) may be due, in addition to peroxynitrite, to the LMW metal-dependent pathway (12). The recent development of IRPs knockout mice (97) offers opportunities to study inflammatory models and nitration in the context of altered iron homeostasis.…”

Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?

“…It was suggested that incorporation of a mutant light chain into ferritin partially compromises the structure and function of the molecule, leading to release of iron, causing oxidative stress and subsequent cell death. Another recent report on mice deficient in iron regulatory protein 2 (IRP2) demonstrating misregulated iron metabolism and neurodegenerative disease also suggests a primary role for iron in neurodegeneration and movement disorder (La Vaute et al ., 2001). These reports suggest that iron may play a direct role in neurodegeneration associated with PD.…”